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Li N, Pang FX, Zhou YW, Ding SC, Shi CJ, Wen RJ, Mai YX, Wu XL, Zhang JF. Polydatin sensitizes osteosarcoma cells to methotrexate through suppressing the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. Bioorg Chem 2025; 162:108583. [PMID: 40381463 DOI: 10.1016/j.bioorg.2025.108583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/28/2025] [Accepted: 05/10/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Osteosarcoma (OS) is a malignant primary tumor in bone tissues, and Methotrexate (MTX) is widely used as a chemotherapeutic drug for OS in clinical treatment. However, MTX resistance is a major challenge for OS patients. Polydatin (PD) is an extract derived from Reynoutria japonica Houtt and has been identified as a potential agent for reversing chemotherapy resistance in cancer. We therefore wondered whether PD could alleviate MTX resistance in OS. METHODS The effect of PD on MTX resistance was investigated. And H19 expression was examined in the PD-treated OS cells. The association between H19 and MTX resistance in osteosarcoma was investigated.The effects of H19 on MTX resistance in osteosarcoma were evaluated by cell proliferation, colony formation, ChIP and western blotting assays. In order to investigate the molecular mechanism of PD underlying methotrexate resistance in OS, the cell proliferation, colony formation, q-PCR and western blotting were examined. RESULTS In the present study, PD was found to act as a novel MTX sensitizer, and significantly enhanced the suppressive effects of MTX on OS in vitro and in vivo. Mechanically, PD was demonstrated to suppress the expression of long non-coding RNA H19 as well as its binding protein histone methyltransferase Enhancer of zeste homolog 2 (EZH2), and thus reduced the trimethylation of histone H3K9 (H3K9me3) and K27 (H3K27me3). Furthermore, H19 knowndown increased the binding ability of H3K9me3 and H3K27me3 with the folate metabolism-related genes RFC-1 and PCFT's promoter, and influenced folate metabolism and MTX resistance. CONCLUSION In conclusion, our results indicated that PD alleviated MTX resistance in OS via the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE The findings of this study validate the function of PD in alleviating MTX resistance, and provide the new insight into developing PD as a promising drug candidate for the MTX resistant OS patients.
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Affiliation(s)
- Nan Li
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Feng-Xiang Pang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, PR China
| | - Yu-Wan Zhou
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China
| | - Shou-Chang Ding
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China
| | - Chuan-Jian Shi
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China; State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, China
| | - Rui-Jia Wen
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Yong-Xin Mai
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Xian-Lin Wu
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China
| | - Jin-Fang Zhang
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, PR China.
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Yuan H, Liu Y, Jia Y, Yang X, Yang D, Dong M, Tang X. PWRN1 low expression facilitates cancer progression and is an unfavorable prognosis factor in breast cancer. Discov Oncol 2025; 16:708. [PMID: 40343594 PMCID: PMC12064524 DOI: 10.1007/s12672-025-02538-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 04/29/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) has a poor prognosis due to metastasis and recurrence. The LncRNA PWRN1 is lowly expressed in breast cancer, so we investigated the regulatory mechanism and prognostic value of PWRN1 in TNBC. METHODS 135 TNBC patients were included. PWRN1 levels and miR-21-5p level were analyzed by RT-qPCR. Independent prognostic factors for TNBC were analyzed using multifactorial Cox regression. CCK-8 was used to test the proliferative capacity of cells. The effects of PWRN1 and miR-21-5p on cell migration and invasive properties were analyzed by Transwell, and their target binding relationship was reported by DLR assay. RESULTS PWRN1 was lowly expressed in TNBC patients, while miR-21-5p was highly expressed. PWRN1 expressions were downregulated and miR-21-5p levels were upregulated in TNBC tissues. miR-21-5p is a downstream target gene of PWRN1 and their expression is negatively correlated. Overexpression of PWRN1 led to low expression of miR-21-5p, which reduced cell proliferation, migration, and invasion. In addition, PWRN1 was an independent prognostic factor. Patients in the PWRN1 low expression group had shorter overall survival. CONCLUSIONS PWRN1 may be a prognostic marker for TNBC. Overexpression of PWRN1 leads to low expression of miR-21-5p, which affects cell proliferation, migration, and invasive behaviors, thereby preventing poor prognosis in TNBC patients.
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Affiliation(s)
- Hubao Yuan
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Yuanwei Liu
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Yong Jia
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Xiaodong Yang
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Dezhen Yang
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Ming Dong
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China
| | - Xin Tang
- Department of Surgical Oncology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Vice No. 2, Weiyang West Road, Qindu District, Xianyang City, 712000, Shaanxi Province, China.
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Li J, Li Y, Fu L, Chen H, Du F, Wang Z, Zhang Y, Huang Y, Miao J, Xiao Y. Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review). Int J Oncol 2025; 66:35. [PMID: 40116120 PMCID: PMC12002672 DOI: 10.3892/ijo.2025.5741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/07/2025] [Indexed: 03/23/2025] Open
Abstract
The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.
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Affiliation(s)
- Junxin Li
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Yanyu Li
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Lin Fu
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Huiling Chen
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Fei Du
- Department of Pharmacy, The Fourth Affiliated Hospital of Southwest Medical University, Meishan, Sichuan 64200, P.R. China
| | - Zhongshu Wang
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Yan Zhang
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Yu Huang
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Jidong Miao
- Department of Oncology, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
| | - Yi Xiao
- Department of Pharmacy, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China
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Zhou H, Gao Z, Wu X, Wang Y, Zhang L. CSF2 promotes chemoresistance in colorectal cancer by regulating Notch pathway. Discov Oncol 2025; 16:495. [PMID: 40202620 PMCID: PMC11981976 DOI: 10.1007/s12672-025-02285-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 04/01/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Increasing evidence suggests that resistance to 5-fluorouracil (5FU) and oxaliplatin (OXP) in colorectal cancer (CRC) is linked to poor prognosis. This study aimed to probe the effect of colony-stimulating factor 2 (CSF2) on the resistance of CRC to 5FU and OXP. METHODS The expression of CSF2 in CRC and the impact of abnormal CSF2 expression on the prognosis of CRC patients were analyzed using bioinformatics. The half-maximal inhibitory concentrations (IC50) of 5FU and OXP on CRC cells were determined using the CCK-8 assay. Apoptosis in CRC cells was assessed through flow cytometry. mRNA and protein levels were measured using qRT-PCR and western blot, respectively. Gene Set Enrichment Analysis (GSEA) was conduced to investigate the signaling pathways regulated by CSF2 in CRC. The Notch pathway activator Jagged-1 (JAG) was employed to verify whether CSF2 influences the resistance of CRC cells to 5-FU and OXP by modulating the Notch signaling pathway. RESULTS High expression of CSF2 is associated with poor prognosis in CRC patients. CSF2 is downregulated in CRC cells that resistance to 5-FU and OXP. Silencing CSF2 inhibits resistance to 5FU and OXP, reduces the survival of resistant CRC cells, and promotes apoptosis. CSF2 activates the Notch signaling pathway, which is highly expressed in CRC resistant cells; conversely, silencing CSF2 inhibits the activation of this pathway. Treatment with JAG reversed the effects of CSF2 silencing on resistance to 5FU and OXP in CRC cells. CONCLUSION The silencing of CSF2 inhibited the resistance of CRC cells to 5FU and OXP by regulating the Notch signaling pathway.
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Affiliation(s)
- Hairong Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, No.287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Zhenyuan Gao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, No.287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Xiao Wu
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, No.287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Yaping Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, No.287 Changhuai Road, Bengbu, 233004, Anhui, China
| | - Lu Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, No.287 Changhuai Road, Bengbu, 233004, Anhui, China.
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Gong L, Zhang H, Liu Y, Wang X, Xia R. Interactions Between Non-Coding RNAs and HIF-1alpha in the Context of Colorectal Cancer. Biomolecules 2025; 15:510. [PMID: 40305214 PMCID: PMC12024830 DOI: 10.3390/biom15040510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/30/2025] [Indexed: 05/02/2025] Open
Abstract
Hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular adaptation to hypoxia, drives colorectal cancer (CRC) progression by fueling angiogenesis, metastasis, and therapy resistance. Emerging evidence delineates intricate crosstalk between non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, and circular RNAs-and HIF-1α, forming bidirectional regulatory networks that orchestrate CRC pathogenesis. By interacting with HIF-1α, these non-coding RNAs contribute to the orchestration of the aggressive hypoxic tumor microenvironment. Recent studies have evaluated the clinical potential of lncRNAs and miRNAs in the realms of non-invasive liquid biopsies and RNA-targeted therapies. This review offers a comprehensive synthesis of recent investigations into the mechanisms by which lncRNAs and miRNAs interact with HIF-1α to modulate CRC progression. Additionally, we further explore the clinical implications of ncRNA/HIF-1α crosstalk, emphasizing their potential as diagnostic biomarkers and therapeutic targets, while also spotlighting intriguing and promising areas of ncRNA research. Methods: In this study, our search strategy employed in databases such as PubMed, Web of Science, and EMBASE is as follows: we will specify search terms, including combinations of "non-coding RNA", "HIF-1α", and "colorectal cancer", along with a date range for the literature search (for example, from 2000 to 2025) to capture the most relevant and up-to-date research.
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Affiliation(s)
| | | | | | - Xianwang Wang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (L.G.); (H.Z.); (Y.L.)
| | - Ruohan Xia
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (L.G.); (H.Z.); (Y.L.)
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Niu YR, Xiang MD, Yang WW, Fang YT, Qian HL, Sun YK. NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer. World J Gastroenterol 2025; 31:100785. [PMID: 40124268 PMCID: PMC11924001 DOI: 10.3748/wjg.v31.i11.100785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/13/2024] [Accepted: 02/13/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells. AIM To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells. METHODS We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays. RESULTS Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition. CONCLUSION SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.
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Affiliation(s)
- Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mi-Dan Xiang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hai-Li Qian
- National Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Xu L, Shen Y, Zhang C, Shi T, Sheng X. Exploring the Link Between Noncoding RNAs and Glycolysis in Colorectal Cancer. J Cell Mol Med 2025; 29:e70443. [PMID: 39993964 PMCID: PMC11850098 DOI: 10.1111/jcmm.70443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/22/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
Glycolysis is implicated in the onset and progression of colorectal cancer (CRC) through its influence on the proliferation, invasiveness, chemoresistance and immune system evasion of neoplasm cells. Increasing evidence has shown that the abnormal expression of noncoding RNAs (ncRNAs), especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in CRC is closely related to glycolysis. In this review, we present a synthesis of the latest research insights into the modulatory roles and distinct pathways of ncRNAs in the glycolytic process in CRC. This knowledge may pave the way for identifying novel therapeutic targets, as well as novel prognostic and diagnostic biomarkers for CRC.
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Affiliation(s)
- Liang Xu
- Neonatal Department, Suzhou Ninth People's HospitalSuzhou Ninth Hospital Affiliated to Soochow UniversitySuzhouJiangsuChina
| | - Yu Shen
- Department of General Surgery, Suzhou Ninth People's HospitalSuzhou Ninth Hospital Affiliated to Soochow UniversitySuzhouJiangsuChina
| | - Chuanqiang Zhang
- Department of General SurgeryThe Affiliated Jiangsu Shengze Hospital of Nanjing Medical UniversitySuzhouChina
- Shengze Clinical Medical CollegeKangda College of Nanjing Medical UniversityNanjingChina
| | - Tongguo Shi
- Jiangsu Institute of Clinical ImmunologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xuejuan Sheng
- Health Management Center, Suzhou Ninth People's HospitalSuzhou Ninth Hospital Affiliated to Soochow UniversitySuzhouJiangsuChina
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Jiang H, Shen H, Xu X, Liu Y, Dong Y, Jiang J. Clinical diagnostic value and potential regulatory mechanisms of lncRNA NOP14-AS1 in chronic kidney disease. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2025:1-18. [PMID: 39862153 DOI: 10.1080/15257770.2025.2456794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/02/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025]
Abstract
In the early stages, chronic kidney disease (CKD) can be asymptomatic, marking diagnosis difficult. This study aimed to investigate the diagnostic role and potential regulatory mechanisms of nucleolar protein 14 (NOP14) -antisense RNA 1 (AS1) in patients with CKD. Herein, 68 patients with CKD, 65 patients with CKD undergoing peridialysis, and 80 healthy adults were included. The real-time reverse transcription-quantitative polymerase chain reaction was performed to assess NOP14-AS1 levels, and its diagnostic value was evaluated using receiver operating characteristic curves. Additionally, cell proliferation and apoptosis were assessed by Cell Counting Kit-8 assay. and flow cytometry, respectively. Oxidative stress levels were determined using superoxide dismutase and malondialdehyde MDA kits, and the dual-luciferase reporter assay was performed to determine the relationship between NOP14-AS1 and microRNA-326 (miR-326) target binding. Lastly, the potential mechanism underlying miR-326 target gene regulation in CKD progression were explored utilizing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Notably, patients with CKD exhibited decreasedNOP14-AS1 levels and upregulated miR-326 levels. NOP14-AS1 and miR-326 exhibited combined effects on cell proliferation, apoptosis, inflammatory factors, and oxidative stress levels. Furthermore, the target genes of miR-326 showed enrichment in CKD-associated rat sarcoma and phosphoinositide 3-kinase protein kinase B pathways. Altogether, the findings of this study show the potential of NOP14-AS1 as a diagnostic marker in CKD. Overall, NOP14-AS1 regulates the miR-326 expression, which, in turn, regulates various miR-326 target gene-associated signaling pathways, thereby affecting the occurrence and development of CKD.
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Affiliation(s)
- Hongfang Jiang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Huajuan Shen
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Xiujun Xu
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Yanna Liu
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Yongze Dong
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Jiaxiang Jiang
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
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Hao X, Gao Z, Hu M. Anti-tumor role and molecular mechanism of vanillic acid. Discov Oncol 2025; 16:20. [PMID: 39775208 PMCID: PMC11711440 DOI: 10.1007/s12672-025-01746-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025] Open
Abstract
Vanillic Acid (VA) is an aromatic acid extracted from traditional Chinese medicine such as Angelica sinensis and Panax ginseng, which has demonstrated potent anti-cancer activity, inhibiting the onset and progression of various malignant tumors. This review highlights the principal mechanism by which VA exerts its anticancer activity, including apoptosis induction, specifically promoting the generation of intracellular reactive oxygen species (ROS), which in turn triggers mitochondrial apoptosis. Furthermore, VA disrupts the cancer cell cycle, arresting most cancer cells at the G1 phase, curtails cell migration, invasion, angiogenesis, and potentiates the therapeutic efficacy of chemotherapeutic drugs, all while minimizing adverse reactions. This paper offers a comprehensive review of VA's anti-tumor effects and underlying mechanisms, aiming to provide some references for scientists and clinical physicians in the research of anti-tumor therapeutic strategies.
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Affiliation(s)
- Xunxing Hao
- Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shangdong, China
| | - Zhixiao Gao
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mingzhe Hu
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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10
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Gu J, Xiao X, Zou C, Mao Y, Jin C, Fu D, Li R, Li H. Ubiquitin-specific protease 7 maintains c-Myc stability to support pancreatic cancer glycolysis and tumor growth. J Transl Med 2024; 22:1135. [PMID: 39707401 PMCID: PMC11662425 DOI: 10.1186/s12967-024-05962-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/11/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND The typical pathological feature of pancreatic ductal adenocarcinoma (PDAC) is a significant increase in stromal reaction, leading to a hypoxic and poorly vascularized tumor microenvironment. Tumor cells undergo metabolic reprogramming, such as the Warburg effect, yet the underlying mechanisms are not fully understood. METHODS Interference and overexpression experiments were conducted to analyze the in vivo and in vitro effects of USP7 on the growth and glycolysis of tumor cells. Small-molecule inhibitors of USP7 and transgenic mouse models of PDAC were employed to assess the consequences of targeting USP7 in PDAC. The molecular mechanism underlying USP7-induced c-Myc stabilization was determined by RNA sequencing, co-IP and western blot analyses. RESULTS USP7 is abnormally overexpressed in PDAC and predicts a poor prognosis. Hypoxia and extracellular matrix stiffness can induce USP7 expression in PDAC cells. Genetic silencing of USP7 inhibits the glycolytic phenotypes in PDAC cells, while its overexpression has the opposite effect, as demonstrated by glucose uptake, lactate production, and extracellular acidification rate. Importantly, USP7 promotes PDAC tumor growth in a glycolysis-dependent manner. The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC. In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression. Mechanistically, USP7 interacts with c-Myc, enhancing its stability and expression, which in turn upregulates expression of glycolysis-related genes. CONCLUSIONS This study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment.
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Affiliation(s)
- Jichun Gu
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xi Xiao
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China
| | - Caifeng Zou
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yishen Mao
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chen Jin
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Deliang Fu
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Rongkun Li
- Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
| | - Hengchao Li
- Department of Pancreatic surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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Xu M, Li X, Yuan C, Zhu T, Wang M, Zhu Y, Duan Y, Yao J, Luo B, Wang Z, Yin S, Zhao Y. Ursolic Acid Inhibits Glycolysis of Ovarian Cancer via KLF5/PI3K/AKT Signaling Pathway. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:2211-2231. [PMID: 39614414 DOI: 10.1142/s0192415x2450085x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Glycolysis is one of the key metabolic reprogramming characteristics of ovarian cancer. Ursolic Acid (UA), as a natural compound, exerts a beneficial regulatory effect on tumor metabolism. In this study, we have confirmed through RNA-seq analysis and a series of in vitro and in vivo functional experiments that UA significantly inhibits ovarian cancer cell proliferation, promotes tumor apoptosis, and reduces glycolysis levels. Additionally, it demonstrates synergistic therapeutic effects with cisplatin in both in vitro and in vivo experiments. Furthermore, at the molecular level, we found that UA inhibits glycolysis in ovarian cancer by binding to the transcription factor KLF5 and blocking the transcriptional expression of the downstream PI3K/AKT signaling pathway, thereby exerting its therapeutic effect. In conclusion, our research indicates that UA can inhibit the proliferation, apoptosis, and glycolysis levels of ovarian cancer cells through the KLF5/PI3K/AKT signaling axis. Our findings offer a new perspective on the therapeutic application of the natural compound UA in ovarian cancer and support its potential development as a candidate for chemotherapy.
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Affiliation(s)
- Meng Xu
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Xiaoqi Li
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Centre, Shanghai 200032, P. R. China
| | - Chenyue Yuan
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Tingting Zhu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, P. R. China
| | - Mengfei Wang
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Ying Zhu
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Yanqiu Duan
- Central Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Jialiang Yao
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Bin Luo
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Ziliang Wang
- Cancer Institute, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P. R. China
| | - Sheng Yin
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yuqing Zhao
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, P. R. China
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12
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Luo S, Yue M, Wang D, Lu Y, Wu Q, Jiang J. Breaking the barrier: Epigenetic strategies to combat platinum resistance in colorectal cancer. Drug Resist Updat 2024; 77:101152. [PMID: 39369466 DOI: 10.1016/j.drup.2024.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/22/2024] [Accepted: 09/20/2024] [Indexed: 10/08/2024]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Platinum-based drugs, such as cisplatin and oxaliplatin, are frontline chemotherapy for CRC, effective in both monotherapy and combination regimens. However, the clinical efficacy of these treatments is often undermined by the development of drug resistance, a significant obstacle in cancer therapy. In recent years, epigenetic alterations have been recognized as key players in the acquisition of resistance to platinum drugs. Targeting these dysregulated epigenetic mechanisms with small molecules represents a promising therapeutic strategy. This review explores the complex relationship between epigenetic changes and platinum resistance in CRC, highlighting current epigenetic therapies and their effectiveness in countering resistance mechanisms. By elucidating the epigenetic underpinnings of platinum resistance, this review aims to contribute to ongoing efforts to improve treatment outcomes for CRC patients.
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Affiliation(s)
- Shiwen Luo
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Ming Yue
- Department of Pharmacy, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
| | - Dequan Wang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Yukang Lu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Qingming Wu
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China; Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, Wuhan 430065, China.
| | - Jue Jiang
- Institute of Infection, Immunology and Tumor Microenvironment, School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China.
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13
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Wang Q, Ying X, Huang Q, Wang Z, Duan S. Exploring the role of tRNA-derived small RNAs (tsRNAs) in disease: implications for HIF-1 pathway modulation. J Mol Med (Berl) 2024; 102:973-985. [PMID: 38850298 DOI: 10.1007/s00109-024-02458-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 04/26/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024]
Abstract
The tRNA-derived small RNAs (tsRNAs) can be categorized into two main groups: tRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). Each group possesses specific molecular sizes, nucleotide compositions, and distinct physiological functions. Notably, hypoxia-inducible factor-1 (HIF-1), a transcriptional activator dependent on oxygen, comprises one HIF-1β subunit and one HIF-α subunit (HIF-1α/HIF-2α/HIF-3α). The activation of HIF-1 plays a crucial role in gene transcription, influencing key aspects of cancer biology such as angiogenesis, cell survival, glucose metabolism, and invasion. The involvement of HIF-1α activation has been demonstrated in numerous human diseases, particularly cancer, making HIF-1 an attractive target for potential disease treatments. Through a series of experiments, researchers have identified two tiRNAs that interact with the HIF-1 pathway, impacting disease development: 5'tiRNA-His-GTG in colorectal cancer (CRC) and tiRNA-Val in diabetic retinopathy (DR). Specifically, 5'tiRNA-His-GTG promotes CRC development by targeting LATS2, while tiRNA-Val inhibits Sirt1, leading to HIF-1α accumulation and promoting DR development. Clinical data have further indicated that certain tsRNAs' expression levels are associated with the prognosis and pathological features of CRC patients. In CRC tumor tissues, the expression level of 5'tiRNA-His-GTG is significantly higher compared to normal tissues, and it shows a positive correlation with tumor size. Additionally, KEGG analysis has revealed multiple tRFs involved in regulating the HIF-1 pathway, including tRF-Val-AAC-016 in diabetic foot ulcers (DFU) and tRF-1001 in pathological ocular angiogenesis. This comprehensive article reviews the biological functions and mechanisms of tsRNAs related to the HIF-1 pathway in diseases, providing a promising direction for subsequent translational medicine research.
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Affiliation(s)
- Qurui Wang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China
| | - Xiaowei Ying
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China
| | - Qinyuan Huang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China
| | - Zehua Wang
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China
| | - Shiwei Duan
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China.
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China.
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Xu Q, Gao J, Zhao R, Li H, Cui H, Yuan Z, Ren H, Cao B, Wei B. Akkermansia muciniphila-derived pentadecanoic acid enhances oxaliplatin sensitivity in gastric cancer by modulating glycolysis. Pharmacol Res 2024; 206:107278. [PMID: 38908613 DOI: 10.1016/j.phrs.2024.107278] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/12/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Accumulating evidence has proved the close association between alterations in gut microbiota and resistance to chemotherapeutic drugs. However, the potential roles of gut microbiota in regulating oxaliplatin sensitivity in gastric cancer (GC) have not been investigated before. We first found that antibiotic treatment diminished the therapeutic efficacy of oxaliplatin in a GC mouse model. Importantly, this effect could be transmitted to germ-free mice via fecal microbiota transplantation, indicating a potential role of gut microbiota modulation in oxaliplatin efficacy. Further, metagenomics data showed that Akkermansia muciniphila (A. muciniphila) ranked first among the bacterial species with decreased relative abundances after antibiotic treatment. Metabolically active A. muciniphila promotes oxaliplatin efficacy. As shown by metabolomics analysis, the metabolic pattern of gut microbiota was disrupted with significantly downregulated levels of pentadecanoic acid (PEA), and the use of PEA significantly promoted oxaliplatin efficacy. Mechanistically, FUBP1 positively regulated aerobic glycolysis of GC cells to hinder the therapeutic efficacy of oxaliplatin. A. muciniphila-derived PEA functioned as an inhibitory factor of glycolysis by directly antagonizing the activity of FUBP1, which potentiated GC responses to oxaliplatin. Our research suggested a key role for intestinal A. muciniphila and its metabolite PEA in promoting oxaliplatin efficacy, thus providing a new perspective for probiotic and prebiotic intervention in GC patients during chemotherapy.
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Affiliation(s)
- Qixuan Xu
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Jingwang Gao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Ruiyang Zhao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Hanghang Li
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Hao Cui
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; School of Medicine, Nankai University, Tianjin, China
| | - Zhen Yuan
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; School of Medicine, Nankai University, Tianjin, China
| | - Huiguang Ren
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Bo Cao
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.
| | - Bo Wei
- Department of General Surgery, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.
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15
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Shi S, Liang H, Huang Q, Sun X. Identification of Novel Prognostic Signature of Recurrent Low-Grade Glioma. World Neurosurg 2024:S1878-8750(24)01287-7. [PMID: 39069129 DOI: 10.1016/j.wneu.2024.07.147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/18/2024] [Accepted: 07/20/2024] [Indexed: 07/30/2024]
Abstract
OBJECTIVES The prognosis of patients with recurrent low-grade glioma (rLGG) varies greatly. Some patients can survive >10 years after recurrence, whereas other patients have <1 year of survival. METHODS To identify the related risk factors affecting the prognosis of patients with rLGG, we performed a series of bioinformatics analyses on RNA sequencing data of rLGG based on the Chinese Glioma Genome Altas database. RESULTS We constructed a 12-gene prognostic signature, dividing all the patients with rLGG into high- and low-risk subgroups. The result showed an excellent predictive effect in both the training cohort and the validation cohort using LASSO-Cox regression. Moreover, multivariate Cox analysis identified 4 independent prognostic factors of rLGG; among them, ZCWPW1 is identified as a high-value protective factor. CONCLUSIONS In all, this prognostic model displayed robust predictive capability for the overall survival of patients with rLGG, providing a new monitoring method for rLGG. The 4 independent prognostic factors, especially ZCWPW1, can be potential targets for rLGG, bringing new possibilities for the treatment of patients with rLGG.
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Affiliation(s)
- Shenbao Shi
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hui Liang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Qinhong Huang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xinlin Sun
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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16
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Shen Y, Wang Y, Wang SY, Li C, Han FJ. Research progress on the application of organoids in gynecological tumors. Front Pharmacol 2024; 15:1417576. [PMID: 38989138 PMCID: PMC11234177 DOI: 10.3389/fphar.2024.1417576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/05/2024] [Indexed: 07/12/2024] Open
Abstract
Organoids are in vitro 3D models that maintain their own tissue structure and function. They largely overcome the limitations of traditional tumor models and have become a powerful research tool in the field of oncology in recent years. Gynecological malignancies are major diseases that seriously threaten the life and health of women and urgently require the establishment of models with a high degree of similarity to human tumors for clinical studies to formulate individualized treatments. Currently, organoids are widely studied in exploring the mechanisms of gynecological tumor development as a means of drug screening and individualized medicine. Ovarian, endometrial, and cervical cancers as common gynecological malignancies have high morbidity and mortality rates among other gynecological tumors. Therefore, this study reviews the application of modelling, drug efficacy assessment, and drug response prediction for ovarian, endometrial, and cervical cancers, thereby clarifying the mechanisms of tumorigenesis and development, and providing precise treatment options for gynecological oncology patients.
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Affiliation(s)
- Ying Shen
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yu Wang
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Si-Yu Wang
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Chan Li
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Feng-Juan Han
- The First School of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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17
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Gao H, Xi Z, Dai J, Xue J, Guan X, Zhao L, Chen Z, Xing F. Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options. Mol Cancer 2024; 23:88. [PMID: 38702734 PMCID: PMC11067278 DOI: 10.1186/s12943-024-02005-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 04/16/2024] [Indexed: 05/06/2024] Open
Abstract
Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.
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Affiliation(s)
- Hongli Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Zhuo Xi
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Jingwei Dai
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xin Guan
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Liang Zhao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
| | - Fei Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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18
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Yan S, He Y, Zhu Y, Ye W, Chen Y, Zhu C, Zhan F, Ma Z. Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research. Front Cell Dev Biol 2024; 12:1384450. [PMID: 38638528 PMCID: PMC11024315 DOI: 10.3389/fcell.2024.1384450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/22/2024] [Indexed: 04/20/2024] Open
Abstract
Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients' tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.
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Affiliation(s)
- Sicheng Yan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuxuan He
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuehong Zhu
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wangfang Ye
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Chen
- Department of Colorectal Surgery, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, China
| | - Cong Zhu
- Department of Colorectal Surgery, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, China
| | - Fuyuan Zhan
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhihong Ma
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, The Affiliated Central Hospital of Huzhou University, Huzhou, China
- School of Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, China
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19
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Ma X, Wang Q, Li G, Li H, Xu S, Pang D. Cancer organoids: A platform in basic and translational research. Genes Dis 2024; 11:614-632. [PMID: 37692477 PMCID: PMC10491878 DOI: 10.1016/j.gendis.2023.02.052] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 02/16/2023] [Indexed: 09/12/2023] Open
Abstract
An accumulation of previous work has established organoids as good preclinical models of human tumors, facilitating translation from basic research to clinical practice. They are changing the paradigm of preclinical cancer research because they can recapitulate the heterogeneity and pathophysiology of human cancers and more closely approximate the complex tissue environment and structure found in clinical tumors than in vitro cell lines and animal models. However, the potential applications of cancer organoids remain to be comprehensively summarized. In the review, we firstly describe what is currently known about cancer organoid culture and then discuss in depth the basic mechanisms, including tumorigenesis and tumor metastasis, and describe recent advances in patient-derived tumor organoids (PDOs) for drug screening and immunological studies. Finally, the present challenges faced by organoid technology in clinical practice and its prospects are discussed. This review highlights that organoids may offer a novel therapeutic strategy for cancer research.
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Affiliation(s)
- Xin Ma
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Qin Wang
- Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
- Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang 150086, China
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Guozheng Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Hui Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
- Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang 150086, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
- Sino-Russian Medical Research Center, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
- Heilongjiang Academy of Medical Sciences, Harbin, Heilongjiang 150086, China
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20
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Zhang M, Wu Y, Mou J, Yao Y, Wen P, Liu X, Shang S, Kang X, Tian J, Liu Y, Lv E, Wang L. The global landscape of immune-derived lncRNA signature in colorectal cancer. Heliyon 2024; 10:e25568. [PMID: 38420407 PMCID: PMC10900961 DOI: 10.1016/j.heliyon.2024.e25568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 01/12/2024] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a highly heterogeneous cancer. This heterogeneity has an impact on the efficacy of immunotherapy. Long noncoding RNAs (lncRNAs) have been found to play regulatory functions in cancer immunity. However, the global landscape of immune-derived lncRNA signatures has not yet been explored in colorectal cancer. METHODS In this study, we applied DESeq2 to identify differentially expressed lncRNAs in colon cancer. Next, we performed an integrative analysis to globally identify immune-driven lncRNA markers in CRC, including immune-associated pathways, tumor immunogenomic features, tumor-infiltrating immune cells, immune checkpoints, microsatellite instability (MSI) and tumor mutation burden (TMB). RESULTS We also identified dysregulated lncRNAs, such as LINC01354 and LINC02257, and their clinical relevance in CRC. Our findings revealed that the differentially expressed lncRNAs were closely associated with immune pathways. In addition, we found that RP11-354P11.3 and RP11-545G3.1 had the highest association with the immunogenomic signature. As a result, these signatures could serve as markers to assess immunogenomic activity in CRC. Among the immune cells, resting mast cells and M0 macrophages had the highest association with lncRNAs in CRC. The AC006129.2 gene was significantly associated with several immune checkpoints, for example, programmed cell death protein 1 (PD-1) and B and T lymphocyte attenuator (BTLA). Therefore, the AC006129.2 gene could be targeted to regulate the condition of immune cells or immune checkpoints to enhance the efficacy of immunotherapy in CRC patients. Finally, we identified 15 immune-related lncRNA-generated open reading frames (ORFs) corresponding to 15 cancer immune epitopes. CONCLUSION In conclusion, we provided a genome-wide immune-driven lncRNA signature for CRC that might provide new insights into clinical applications and immunotherapy.
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Affiliation(s)
- Mengying Zhang
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yifei Wu
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jingyi Mou
- Department of Clinical Medicine, School of 1st Clinical Medicine, Xuzhou Medical University, Xuzhou, China
| | - Yang Yao
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Pengbo Wen
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xin Liu
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shipeng Shang
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xingxing Kang
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiaqi Tian
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yan Liu
- School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Enhui Lv
- School of Medical Information and Engineering, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Liang Wang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- Division of Microbiology and Immunology, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
- School of Agriculture and Food Sustainability, University of Queensland, Brisbane, Queensland, Australia
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21
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Gao A, Zhang M, Zhu SQ, Zou S, Chen H, Li X, He C, Zhou L, Mei Y, Ding W, Zhou J, Zhou Y, Cao Y. DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α. Cell Death Dis 2024; 15:171. [PMID: 38402183 PMCID: PMC10894303 DOI: 10.1038/s41419-024-06552-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 02/05/2024] [Accepted: 02/09/2024] [Indexed: 02/26/2024]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. However, the underlying mechanism is not well understood. In this study, we utilized ChIP-PCR and luciferase reporter assays to investigate the binding of HIF-1α to the promoter of the Pol ι gene. Transwell, wound healing, and mouse models were employed to assess the impact of Pol ι and HIF-1α on the motility of ESCC cells. Co-immunoprecipitation and Western blot were carried out to explore the interaction between Pol ι and HIF-1α, while qRT-PCR and Western blot were conducted to confirm the regulation of Pol ι and HIF-1α on their downstream targets. Our results demonstrate that HIF-1α activates the transcription of the Pol ι gene in ESCC cells under hypoxic conditions. Furthermore, the knockdown of Pol ι impeded HIF-1α-induced invasion and metastasis. Additionally, we found that Pol ι regulates the expression of genes involved in epithelial-mesenchymal transition (EMT) and initiates EMT through the stabilization of HIF-1α. Mechanistically, Pol ι maintains the protein stability of HIF-1α by recruiting USP7 to mediate the deubiquitination of HIF-1α, with the residues 446-578 of Pol being crucial for the interaction between Pol ι and USP7. Collectively, our findings unveil a novel feedforward molecular axis of HIF-1α- Pol ι -USP7 in ESCC that contributes to ESCC metastasis. Hence, our results present an attractive target for intervention in ESCC.
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Affiliation(s)
- Aidi Gao
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Mingxia Zhang
- Department of Radiation Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Shuang Qi Zhu
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Shitao Zou
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Hengrui Chen
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Xiaoqin Li
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Chao He
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Liangsu Zhou
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Yan Mei
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China
| | - Weiqun Ding
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Jundong Zhou
- Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, P.R. China.
| | - Yue Zhou
- Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
| | - Yuandong Cao
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China.
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22
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Qu S, Xu R, Yi G, Li Z, Zhang H, Qi S, Huang G. Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine. MOLECULAR BIOMEDICINE 2024; 5:6. [PMID: 38342791 PMCID: PMC10859360 DOI: 10.1186/s43556-023-00165-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 12/08/2023] [Indexed: 02/13/2024] Open
Abstract
Cancer is associated with a high degree of heterogeneity, encompassing both inter- and intra-tumor heterogeneity, along with considerable variability in clinical response to common treatments across patients. Conventional models for tumor research, such as in vitro cell cultures and in vivo animal models, demonstrate significant limitations that fall short of satisfying the research requisites. Patient-derived tumor organoids, which recapitulate the structures, specific functions, molecular characteristics, genomics alterations and expression profiles of primary tumors. They have been efficaciously implemented in illness portrayal, mechanism exploration, high-throughput drug screening and assessment, discovery of innovative therapeutic targets and potential compounds, and customized treatment regimen for cancer patients. In contrast to conventional models, tumor organoids offer an intuitive, dependable, and efficient in vitro research model by conserving the phenotypic, genetic diversity, and mutational attributes of the originating tumor. Nevertheless, the organoid technology also confronts the bottlenecks and challenges, such as how to comprehensively reflect intra-tumor heterogeneity, tumor microenvironment, tumor angiogenesis, reduce research costs, and establish standardized construction processes while retaining reliability. This review extensively examines the use of tumor organoid techniques in fundamental research and precision medicine. It emphasizes the importance of patient-derived tumor organoid biobanks for drug development, screening, safety evaluation, and personalized medicine. Additionally, it evaluates the application of organoid technology as an experimental tumor model to better understand the molecular mechanisms of tumor. The intent of this review is to explicate the significance of tumor organoids in cancer research and to present new avenues for the future of tumor research.
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Affiliation(s)
- Shanqiang Qu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, China
- Institute of Brain disease, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
| | - Rongyang Xu
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- The First Clinical Medical College of Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Guozhong Yi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, China
- Institute of Brain disease, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
| | - Zhiyong Li
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, China
- Institute of Brain disease, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
| | - Huayang Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Songtao Qi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China.
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, China.
- Institute of Brain disease, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China.
| | - Guanglong Huang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China.
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, China.
- Institute of Brain disease, Nanfang Hospital, Southern Medical University, Guangzhou Dadao Bei Street 1838, Guangzhou, 510515, Guangdong, China.
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23
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Song B, Wei F, Peng J, Wei X, Liu M, Nie Z, Ma Y, Peng T. Icariin Regulates EMT and Stem Cell-Like Character in Breast Cancer through Modulating lncRNA NEAT1/TGFβ/SMAD2 Signaling Pathway. Biol Pharm Bull 2024; 47:399-410. [PMID: 38220208 DOI: 10.1248/bpb.b23-00668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Metastases and drug resistance are the major risk factors associated with breast cancer (BC), which is the most common type of tumor affecting females. Icariin (ICA) is a traditional Chinese medicine compound that possesses significant anticancer properties. Long non-coding RNAs (lncRNAs) are involved in a wide variety of biological and pathological processes and have been shown to modulate the effectiveness of certain drugs in cancer. The purpose of this study was to examine the potential effect of ICA on epithelial mesenchymal transition (EMT) and stemness articulation in BC cells, as well as the possible relationship between its inhibitory action on EMT and stemness with the NEAT1/transforming growth factor β (TGFβ)/SMAD2 pathway. The effect of ICA on the proliferation (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony assays), EMT (Western blotting, immunofluorescence, and wound healing), and stemness (mammosphere formation assays, Western blotting) of BC cells were examined. According to the findings, ICA suppressed the proliferation, EMT, and stem cell-like in MDA-MB-231 cells, and exerted its inhibitory impact by downregulating the TGFβ/SMAD2 signaling pathway. ICA could significantly downregulate the expression of lncRNA NEAT1, and silencing NEAT1 enhanced the effect of ICA in suppressing EMT and expression of different stem cell markers. In addition, silencing NEAT1 was found to attenuate the TGFβ/SMAD2 signaling pathway, thereby improving the inhibitory impact of ICA on stemness and EMT in BC cells. In conclusion, ICA can potentially inhibit the metastasis of BC via affecting the NEAT1/TGFβ/SMAD2 pathway, which provides a theoretical foundation for understanding the mechanisms involved in potential application of ICA for BC therapy.
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Affiliation(s)
- Bo Song
- School of Third Clinical Medicine, Shanxi University of Chinese Medicine
| | - Fuxia Wei
- School of Third Clinical Medicine, Shanxi University of Chinese Medicine
| | - Jiehao Peng
- School of Third Clinical Medicine, Shanxi University of Chinese Medicine
| | - Xiuhong Wei
- School of Basic Medical Sciences, Shanxi University of Chinese Medicine
| | - Mingran Liu
- School of Basic Medical Sciences, Shanxi University of Chinese Medicine
| | - Zhongbiao Nie
- Pharmaceutical Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University
| | - Yanmiao Ma
- School of Basic Medical Sciences, Shanxi University of Chinese Medicine
| | - Tao Peng
- Famous Chinese Medicine Studio, Shanxi Hospital of Integrated Traditional Chinese and Western Medicine
- Shanxi Provincial Key Laboratory of Classical Prescription Strengthening Yang, Shanxi Hospital of Integrated Traditional Chinese and Western Medicine
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24
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Liu N, Chen M. Crosstalk between ferroptosis and cuproptosis: From mechanism to potential clinical application. Biomed Pharmacother 2024; 171:116115. [PMID: 38181713 DOI: 10.1016/j.biopha.2023.116115] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/23/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
Ferroptosis and cuproptosis, regulated forms of cell death resulting from metal ion accumulation, are closely related in terms of occurrence, cell metabolism, signaling pathways, and drug resistance. Notably, it is now understood that these processes play crucial roles in regulating physiological and pathological processes, especially in tumor development. Consequently, ferroptosis and cuproptosis have gained increasing significance as potential targets for anti-cancer drug development. This article systematically outlines the molecular mechanisms and cross-talk components of both ferroptosis and cuproptosis, elucidating their impacts on cancer. Furthermore, it investigates the clinical perspective of targeted ferroptosis and cuproptosis in cancer chemotherapy, immunotherapy, and radiotherapy. Our discussion extends to a comparative analysis of nanoparticles developed based on the mechanisms of ferroptosis and cuproptosis in cancer, contrasting them with current conventional therapies. Opportunities and challenges in cancer treatment are explored, emphasizing the potential therapeutic direction of co-targeting ferroptosis and cuproptosis. The article also attempts to analyze the clinical applications of this co-targeting approach for cancer treatment while summarizing the existing barriers that require overcoming.
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Affiliation(s)
- Na Liu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Minbin Chen
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
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25
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Albadari N, Xie Y, Li W. Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling. Front Pharmacol 2024; 14:1340401. [PMID: 38269272 PMCID: PMC10806212 DOI: 10.3389/fphar.2023.1340401] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
In 2023, colorectal cancer (CRC) is the third most diagnosed malignancy and the third leading cause of cancer death worldwide. At the time of the initial visit, 20% of patients diagnosed with CRC have metastatic CRC (mCRC), and another 25% who present with localized disease will later develop metastases. Despite the improvement in response rates with various modulation strategies such as chemotherapy combined with targeted therapy, radiotherapy, and immunotherapy, the prognosis of mCRC is poor, with a 5-year survival rate of 14%, and the primary reason for treatment failure is believed to be the development of resistance to therapies. Herein, we provide an overview of the main mechanisms of resistance in mCRC and specifically highlight the role of drug transports, EGFR, and HGF/c-MET signaling pathway in mediating mCRC resistance, as well as discuss recent therapeutic approaches to reverse resistance caused by drug transports and resistance to anti-EGFR blockade caused by mutations in EGFR and alteration in HGF/c-MET signaling pathway.
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Affiliation(s)
| | | | - Wei Li
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States
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26
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Su Z, Li W, Lei Z, Hu L, Wang S, Guo L. Regulation of Angiogenesis by Non-Coding RNAs in Cancer. Biomolecules 2024; 14:60. [PMID: 38254660 PMCID: PMC10813527 DOI: 10.3390/biom14010060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been identified as crucial regulators of various biological processes through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation. Growing evidence suggests that dysregulation and activation of non-coding RNAs are closely associated with tumor angiogenesis, a process essential for tumor growth and metastasis and a major contributor to cancer-related mortality. Therefore, understanding the molecular mechanisms underlying tumor angiogenesis is of utmost importance. Numerous studies have documented the involvement of different types of non-coding RNAs in the regulation of angiogenesis. This review provides an overview of how non-coding RNAs regulate tumor angiogenesis. Additionally, we discuss emerging strategies that exploit non-coding RNAs for anti-angiogenic therapy in cancer treatment. Ultimately, this review underscores the crucial role played by non-coding RNAs in tumor angiogenesis and highlights their potential as therapeutic targets for anti-angiogenic interventions against cancer.
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Affiliation(s)
- Zhiyue Su
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wenshu Li
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Zhe Lei
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Lin Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China
| | - Shengjie Wang
- Department of Basic Medicine, Kangda College, Nanjing Medical University, Lianyungang 222000, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
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27
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Sun B, Yue SG. Expression of long noncoding RNA MEG3 and microRNA-302b-3p in colon cancer: Correlation with clinical stage and value in predicing prognosis after surgical treatment. Shijie Huaren Xiaohua Zazhi 2023; 31:981-988. [DOI: 10.11569/wcjd.v31.i23.981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/08/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND More and more long non-coding RNAs and microRNAs have been found to have significant changes in expression levels during the occurrence and development of tumors, which can affect the expression of tumor suppressor genes or oncogenes and play an important role in the proliferation and metastasis of cancer cells.
AIM To investigate the correlation between the expression of long non-coding RNA maternal imprinted gene 3 (LncRNA MEG3) and microRNA (miR)-302b-3p in colon cancer and clinical stage and analyze their value in predicting the prognosis after surgical treatment.
METHODS A total of 97 patients with colon cancer treated at Jinhua Hospital of TCM from January 2017 to March 2022 were selected to compare the expression of LncRNA MEG3 and miR-302b-3p in different tissues, analyze the correlation between the expression of LncRNA MEG3 and miR-302b-3p and clinical pathological characteristics, compare the recurrence in patients with different LncRNA MEG3 and miR-302b-3p expression, analyze the factors affecting the recurrence of colon cancer after surgery, and analyze the impact of the interaction between LncRNA MEG3 and miR-302b-3p on the recurrence of colon cancer. The predictive value of LncRNA MEG3 and miR-302b-3p expression for the recurrence of colon cancer after surgery was evaluated.
RESULTS The expression of LncRNA MEG3 and miR-302b-3p in colon cancer tissues was lower than that in tumor-adjacent tissues (P < 0.05). The expression of LncRNA MEG3 and miR-302b-3p in colon cancer tissues was not correlated with sex, age, or tumor size (P > 0.05), but was correlated with tumor differentiation, clinical stage, and lymph node metastasis (P < 0.05). In colon cancer tissues, the recurrence rate in patients with high LncRNA MEG3 and miR-302b-3p expression was lower than that of patients with lower LncRNA MEG3 and miR-302b-3p expression (P < 0.05). Tumor differentiation degree, clinical stage, and lymph node metastasis were all identified to be risk factors for colon cancer recurrence, and LncRNA MEG3 and miR-302b-3p expression were protective factors for colon cancer recurrence (P < 0.05). The interaction analysis showed that the synergistic effect of simultaneous exposure to LncRNA MEG3 and miR-302b-3p was 15.888 times greater than the effect of exposure to either LncRNA MEG3 or miR-302b-3p alone, and when simultaneously exposing to both, 56.98% of the risk of colon cancer recurrence was attributed to their synergistic effect. The area under the curve (AUC) (95% confidence interval [CI]) of LncRNA MEG3 and miR-302b-3p in predicting the prognosis of colon cancer patients was 0.720 (0.620-0.807) and 0.767 (0.670-0.847), respectively, and that of the combined prediction was 0.892 (0.813-0.946), with a sensitivity and specificity of 92.31% and 83.33%, respectively, which were significantly higher than those of either LncRNA MEG3 or miR-302b-3p alone.
CONCLUSION The down-regulated expression of LncRNA MEG3 and miR-302b-3p in colon cancer is related to clinical stage. Clinical detection of their expression can be used to determine the malignant degree of tumor and predict the prognosis of surgical treatment, thus providing reference for adjustment of clinical treatment plan.
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Affiliation(s)
- Bing Sun
- Second Department of Surgery, Jinhua Hospital of Traditional Chinese Medicine, Jinhua 321017, Zhejiang Province, China
| | - Shi-Guo Yue
- Second Department of Surgery, Jinhua Hospital of Traditional Chinese Medicine, Jinhua 321017, Zhejiang Province, China
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28
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Hussen BM, Abdullah ST, Abdullah SR, Younis YM, Hidayat HJ, Rasul MF, Mohamadtahr S. Exosomal non-coding RNAs: Blueprint in colorectal cancer metastasis and therapeutic targets. Noncoding RNA Res 2023; 8:615-632. [PMID: 37767111 PMCID: PMC10520679 DOI: 10.1016/j.ncrna.2023.09.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is ranked as the world's third-most prevalent cancer, and metastatic CRC considerably increases cancer-related fatalities globally. A number of complex mechanisms that are strictly controlled at the molecular level are involved in metastasis, which is the primary reason for death in people with CRC. Recently, it has become clear that exosomes, which are small extracellular vesicles released by non-tumorous and tumorigenic cells, play a critical role as communication mediators among tumor microenvironment (TME). To facilitate communication between the TME and cancer cells, non-coding RNAs (ncRNAs) play a crucial role and are recognized as potent regulators of gene expression and cellular processes, such as metastasis and drug resistance. NcRNAs are now recognized as potent regulators of gene expression and many hallmarks of cancer, including metastasis. Exosomal ncRNAs, like miRNAs, circRNAs, and lncRNAs, have been demonstrated to influence a number of cellular mechanisms that contribute to CRC metastasis. However, the molecular mechanisms that link exosomal ncRNAs with CRC metastasis are not well understood. This review highlights the essential roles that exosomal ncRNAs play in the progression of CRC metastatic disease and explores the therapeutic choices that are open to patients who have CRC metastases. However, exosomal ncRNA treatment strategy development is still in its early phases; consequently, additional investigation is required to improve delivery methods and find novel therapeutic targets as well as confirm the effectiveness and safety of these therapies in preclinical and clinical contexts.
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Affiliation(s)
- Bashdar Mahmud Hussen
- Department of Biomedical Sciences, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, 44001, Iraq
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Snur Rasool Abdullah
- Medical Laboratory Science, College of Health Sciences, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Yousif Mohammed Younis
- Department of Nursing, College of Nursing, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Mohammed Fatih Rasul
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Sayran Mohamadtahr
- Department of Clinical Analysis, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq
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29
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Liu WF, Zhang QW, Quan B, Zhang F, Li M, Lu SX, Dong L, Yin X, Liu BB. Gas7 attenuates hepatocellular carcinoma progression and chemoresistance through the PI3K/Akt signaling pathway. Cell Signal 2023; 112:110908. [PMID: 37769891 DOI: 10.1016/j.cellsig.2023.110908] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/01/2023] [Accepted: 09/25/2023] [Indexed: 10/03/2023]
Abstract
Growth arrest-specific gene 7 (Gas7) was involved in various cellular functions, although its specific roles and molecular mechanisms in hepatocellular carcinoma (HCC) remained unclear. So the current study was to investigate the role of Gas7 in HCC. Our findings revealed that Gas7 was downregulated in various HCC cell lines and low Gas7 expression was associated with decreased overall survival in patients with HCC. Additionally, our functional assays showed that Gas7 inhibited cell proliferation and migration, induced cell cycle arrest, apoptosis, and autophagy, and enhanced oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway. We also observed that transcription factorSp1 was responsible for inhibiting Gas7. These findings provide insights into the role and elucidated a potential mechanism of Gas7 in HCC progression and metastasis. It was also observed that the Sp1/Gas7/PI3K/Akt axis was critical for malignant phenotype and oxaliplatin sensitivity in HCC. Therefore, Gas7 can be considered as a prognostic predictor and therapeutic target for HCC.
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Affiliation(s)
- Wen-Feng Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qi-Wei Zhang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Bing Quan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Feng Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Shen-Xin Lu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Xin Yin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| | - Bin-Bin Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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30
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Lu Q, Liang Y, Meng X, Zhao Y, Fan H, Hou S. The Role of Long Noncoding RNAs in Intestinal Health and Diseases: A Focus on the Intestinal Barrier. Biomolecules 2023; 13:1674. [PMID: 38002356 PMCID: PMC10669616 DOI: 10.3390/biom13111674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/04/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
The gut is the body's largest immune organ, and the intestinal barrier prevents harmful substances such as bacteria and toxins from passing through the gastrointestinal mucosa. Intestinal barrier dysfunction is closely associated with various diseases. However, there are currently no FDA-approved therapies targeting the intestinal epithelial barriers. Long noncoding RNAs (lncRNAs), a class of RNA transcripts with a length of more than 200 nucleotides and no coding capacity, are essential for the development and regulation of a variety of biological processes and diseases. lncRNAs are involved in the intestinal barrier function and homeostasis maintenance. This article reviews the emerging role of lncRNAs in the intestinal barrier and highlights the potential applications of lncRNAs in the treatment of various intestinal diseases by reviewing the literature on cells, animal models, and clinical patients. The aim is to explore potential lncRNAs involved in the intestinal barrier and provide new ideas for the diagnosis and treatment of intestinal barrier damage-associated diseases in the clinical setting.
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Affiliation(s)
- Qianying Lu
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Yangfan Liang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Xiangyan Meng
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Yanmei Zhao
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Haojun Fan
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Shike Hou
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (X.M.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
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Chen Y, Xu X, Wang Y, Zhang Y, Zhou T, Jiang W, Wang Z, Chang J, Liu S, Chen R, Shan J, Wang J, Wang Y, Li C, Li X. Hypoxia-induced SKA3 promoted cholangiocarcinoma progression and chemoresistance by enhancing fatty acid synthesis via the regulation of PAR-dependent HIF-1a deubiquitylation. J Exp Clin Cancer Res 2023; 42:265. [PMID: 37821935 PMCID: PMC10565972 DOI: 10.1186/s13046-023-02842-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. METHODS Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. RESULTS SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery. CONCLUSION Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.
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Affiliation(s)
- Yananlan Chen
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Xiao Xu
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Yirui Wang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Yaodong Zhang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Tao Zhou
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Wangjie Jiang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Ziyi Wang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Jiang Chang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Shuochen Liu
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Ruixiang Chen
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Jijun Shan
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Jifei Wang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Yuming Wang
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China
| | - Changxian Li
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China.
- Key Laoratory for Liver Transplantation, NHC Key Laboratory of Living Donor Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing Medical University), Nanjing, Jiangsu Province, China.
| | - Xiangcheng Li
- Hepatobiliary Surgery Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, China.
- Key Laoratory for Liver Transplantation, NHC Key Laboratory of Living Donor Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing Medical University), Nanjing, Jiangsu Province, China.
- Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
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Weng G, Tao J, Liu Y, Qiu J, Su D, Wang R, Luo W, Zhang T. Organoid: Bridging the gap between basic research and clinical practice. Cancer Lett 2023; 572:216353. [PMID: 37599000 DOI: 10.1016/j.canlet.2023.216353] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
Nowadays, the diagnosis and treatment system of malignant tumors has increasingly tended to be more precise and personalized while the existing tumor models are still unable to fully meet the needs of clinical practice. Notably, the emerging organoid platform has been proven to have huge potential in the field of basic-translational medicine, which is expected to promote a paradigm shift in personalized medicine. Here, given the unique advantages of organoid platform, we mainly explore the prominent role of organoid models in basic research and clinical practice from perspectives of tumor biology, tumorigenic microbes-host interaction, clinical decision-making, and regenerative strategy. In addition, we also put forward some practical suggestions on how to construct a new generation of organoid platform, which is destined to vigorously promote the reform of basic-translational medicine.
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Affiliation(s)
- Guihu Weng
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Jinxin Tao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Yueze Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Dan Su
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Ruobing Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
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Hamilton DJ, Hein AE, Wuttke DS, Batey RT. The DNA binding high mobility group box protein family functionally binds RNA. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1778. [PMID: 36646476 PMCID: PMC10349909 DOI: 10.1002/wrna.1778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 01/18/2023]
Abstract
Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell-based systems, HMGB-RNA interactions facilitate protein-protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB-RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Dong X, Liao P, Liu X, Yang Z, Wang Y, Zhong W, Wang B. Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer. Int J Mol Sci 2023; 24:12915. [PMID: 37629096 PMCID: PMC10454603 DOI: 10.3390/ijms241612915] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan-Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making.
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Affiliation(s)
- Xiaoqian Dong
- School of Medicine, Nankai University, Tianjin 300071, China; (X.D.)
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Pan Liao
- School of Medicine, Nankai University, Tianjin 300071, China; (X.D.)
| | - Xiaotong Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Zhenni Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Yali Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Bangmao Wang
- School of Medicine, Nankai University, Tianjin 300071, China; (X.D.)
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
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Li S, Wang X, Liu Y, Xiao J, Yi J. The implication of necroptosis-related lncRNAs in orchestrating immune infiltration and predicting therapeutic efficacy in colon adenocarcinoma: an integrated bioinformatic analysis with preliminarily experimental validation. Front Genet 2023; 14:1170640. [PMID: 37600653 PMCID: PMC10433646 DOI: 10.3389/fgene.2023.1170640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/17/2023] [Indexed: 08/22/2023] Open
Abstract
Background: Necroptosis contributes significantly to colon adenocarcinoma (COAD). We aim to assess the relationship between immunoinfiltration and stemness in COAD patients through the development of a risk score profile using necroptosis-related long noncoding RNAs (NRLs). Methods: Our study was based on gene expression data and relevant clinical information from The Cancer Genome Atlas (TCGA). Necroptosis-related genes (NRGs) were obtained from the Kyoto Encyclopedia of Genes and Genome (KEGG) database. Pearson correlation analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) regression were used to determine the NRL prognositic signature (NRLPS). NRLs expression was examined using qRT-PCR method. Several algorithms were used to identify relationships between immune cell infiltration and NRLPS risk scores. Further analysis of somatic mutations, tumor stemness index (TSI), and drug sensitivity were also explored. Results: To construct NRLPS, 15 lncRNAs were investigated. Furthermore, NRLPS patients with high-risk subgroups had lower survival rates than that of patients with low-risk subgroups. Using GSEA analysis, NRL was found to be enriched in Notch, Hedgehog and Smoothened pathways. Immune infiltration analysis showed significant differences in CD8+ T cells, dendritic cell DCs, and CD4+ T cells between the two risk groups. In addition, our NRLPS showed a relevance with the regulation of tumor microenvironment, tumor mutation burden (TMB) and stemness. Finally, NRLPS demonstrated potential applications in predicting the efficacy of immunotherapy and chemotherapy in patients with COAD. Conclusion: Based on NRLs, a prognostic model was developed for COAD patients that allows a personalized tailoring immunotherapy and chemotherapy to be tailored.
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Affiliation(s)
- Shizhe Li
- Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Xiaotong Wang
- Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Yajun Liu
- Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Junbo Xiao
- Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Jun Yi
- Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial People’s Hospital, Changsha, Hunan, China
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Saha G, Roy S, Basu M, Ghosh MK. USP7 - a crucial regulator of cancer hallmarks. Biochim Biophys Acta Rev Cancer 2023; 1878:188903. [PMID: 37127084 DOI: 10.1016/j.bbcan.2023.188903] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/03/2023]
Abstract
Over the course of three decades of study, the deubiquitinase Herpesvirus associated Ubiquitin-Specific Protease/Ubiquitin-Specific Protease 7 (HAUSP/USP7) has gradually come to be recognized as a crucially important molecule in cellular physiology. The fact that USP7 is overexpressed in a number of cancers, including breast, prostate, colorectal, and lung cancers, supports the idea that USP7 is also an important regulator of tumorigenesis. In this review, we discuss USP7's function in relation to the cancer hallmarks described by Hanahan and Weinberg. This post-translational modifier can support increased proliferation, block unfavorable growth signals, stop cell death, and support an unstable cellular genome by manipulating key players in the pertinent signalling circuit. It is interesting to note that USP7 also aids in the stabilization of molecules that support angiogenesis and metastasis. Targeting USP7 has now emerged as a crucial component of USP7 research because pharmacological inhibition of USP7 supports p53-mediated cell cycle arrest and apoptosis. Efficacious USP7 inhibition is currently being investigated in both synthetic and natural compounds, but issues with selectivity and a lack of co-crystal structure have hindered USP7 inhibition from being tested in clinical settings. Moreover, the development of new, more effective USP7 inhibitors and their encouraging implications by numerous groups give us a glimmer of hope for USP7-targeting medications as effective substitutes for hazardous cancer chemotherapeutics.
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Affiliation(s)
- Gouranga Saha
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India
| | - Srija Roy
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, University of Calcutta, Kolkata, PIN - 743372, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India.
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Zheng Z, Wu M, Li H, Xu W, Yang M, Pan K, Ni Y, Jiang T, Zheng H, Jin X, Zhang Y, Ding L, Fu J. Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis. BMC Med 2023; 21:132. [PMID: 37013584 PMCID: PMC10071743 DOI: 10.1186/s12916-023-02826-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 03/09/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. METHODS The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. RESULTS AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. CONCLUSIONS In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance.
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Affiliation(s)
- Zhijian Zheng
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
- Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Ming Wu
- Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Hongyan Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Wenxia Xu
- Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Mengxiang Yang
- Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Kailing Pan
- Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Yuqi Ni
- Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Ting Jiang
- Department of Nuclear Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Hongjuan Zheng
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Xiayun Jin
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Yanfei Zhang
- Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China
| | - Linchao Ding
- Department of Scientific Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China.
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, China.
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Ding LN, Yu YY, Ma CJ, Lei CJ, Zhang HB. SOX2-associated signaling pathways regulate biological phenotypes of cancers. Biomed Pharmacother 2023; 160:114336. [PMID: 36738502 DOI: 10.1016/j.biopha.2023.114336] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
SOX2 is a transcription factor involved in multiple stages of embryonic development. In related reports, SOX2 was found to be abnormally expressed in tumor tissues and correlated with clinical features such as TNM staging, tumor grade, and prognosis in patients with various cancer types. In most cancer types, SOX2 is a tumor-promoting factor that regulates tumor progression and metastasis primarily by maintaining the stemness of cancer cells. In addition, SOX2 also regulates the proliferation, apoptosis, invasion, migration, ferroptosis and drug resistance of cancer cells. However, SOX2 acts as a tumor suppressor in some cases in certain cancer types, such as gastric and lung cancer. These key regulatory functions of SOX2 involve complex regulatory networks, including protein-protein and protein-nucleic acid interactions through signaling pathways and noncoding RNA interactions, modulating SOX2 expression may be a potential therapeutic strategy for clinical cancer patients. Therefore, we sorted out the phenotypes related to SOX2 in cancer, hoping to provide a basis for further clinical translation.
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Affiliation(s)
- L N Ding
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Y Y Yu
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - C J Ma
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - C J Lei
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - H B Zhang
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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He J, Wu W. Comprehensive landscape and future perspectives of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC): Based on a bibliometric analysis. Noncoding RNA Res 2023; 8:33-52. [PMID: 36311994 PMCID: PMC9582894 DOI: 10.1016/j.ncrna.2022.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022] Open
Abstract
This review aimed to use bibliometric analysis to sort out, analyze and summarize the knowledge foundation and hot topics in the field of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC), and point out future trends to inspire related research and innovation. We used CiteSpace to analyze publication outputs, countries, institutions, authors, journals, references, and keywords. Knowledge foundations, hotspots, and future trends were then depicted. The overall research showed the trend of biomedical-oriented multidisciplinary. Much evidence indicates that lncRNA plays the role of oncogene or tumor suppressor in the occurrence and development of CRC. Besides, many lncRNAs have multiple mechanisms. lncRNAs and metastasis of CRC, lncRNAs and drug resistance of CRC, and the clinical application of lncRNAs in CRC are current research hotspots. Through insight into the development trend of lncRNAs in CRC, this study will help researchers extract hidden valuable information for further research.
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Affiliation(s)
- Jia He
- Faculty Affairs and Human Resources Management Department, Southwest Medical University, Luzhou, China
| | - Wenhan Wu
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Chai C, Ji P, Xu H, Tang H, Wang Z, Zhang H, Zhou W. Targeting cancer drug resistance utilizing organoid technology. Biomed Pharmacother 2023; 158:114098. [PMID: 36528918 DOI: 10.1016/j.biopha.2022.114098] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Cancer organoids generated from 3D in vitro cell cultures have contributed to the study of drug resistance. Maintenance of genomic and transcriptomic similarity between organoids and parental cancer allows organoids to have the ability of accurate prediction in drug resistance testing. Protocols of establishing therapy-sensitive and therapy-resistant organoids are concluded in two aspects, which are generated directly from respective patients' cancer and by induction of anti-cancer drug. Genomic and transcriptomic analyses and gene editing have been applied to organoid studies to identify key targets in drug resistance and FGFR3, KHDRBS3, lnc-RP11-536 K7.3 and FBN1 were found to be key targets. Furthermore, mechanisms contributing to resistance have been identified, including metabolic adaptation, activation of DNA damage response, defects in apoptosis, reduced cellular senescence, cellular plasticity, subpopulation interactions and gene fusions. Additionally, cancer stem cells (CSCs) have been verified to be involved in drug resistance utilizing organoid technology. Reversal of drug resistance can be achieved by targeting key genes and CSCs in cancer organoids. In this review, we summarize applications of organoids to cancer drug resistance research, indicating prospects and limitations.
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Affiliation(s)
- Changpeng Chai
- The First Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China; The Forth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Pengfei Ji
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Hao Xu
- The First Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Huan Tang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Zhengfeng Wang
- The First Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Hui Zhang
- The Second Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China.
| | - Wence Zhou
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou 730000, Gansu, China; The Second Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu, China.
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Tao X, Li Y, Fan S, Wu L, Xin J, Su Y, Xian X, Huang Y, Huang R, Fang W, Liu Z. Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2023; 42:12. [PMID: 36627670 PMCID: PMC9830831 DOI: 10.1186/s13046-022-02560-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 12/04/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND LINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small-cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). This study aimed to display reverse data for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD). METHODS LINC00173 was screened from the Gene Expression Omnibus database (GSE43493). The expression level of LINC00173 in LUAD tissues and cell lines was detected using in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Colony formation, cell viability, half-maximal inhibitory concentration, flow cytometry, and xenograft mouse model were used to evaluate the role of LINC00173 in the chemosensitivity of LUAD to DDP. The mechanism of LINC00173 in DDP resistance by mediating miR-1275/PROCA1/ZFP36L2 axis to impair BCL2 mRNA stability was applied, and co-immunoprecipitation, chromatin immunoprecipitation, RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays were performed. RESULTS LINC00173 downregulation in patients with DDP-resistant LUAD was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 expression in LUAD cells enhanced DDP chemoresistance in vivo and in vitro, while restored LINC00173 expression in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated the c-Myc expression. The c-Myc, as an oncogenic transcriptional factor, bound to the promoter of LINC00173 and suppressed its expression. The reduced LINC00173 expression attenuated the adsorption of oncogenic miR-1275, downregulating the expression of miR-1275 target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3' untranslated region of BCL2, reducing the stability of BCL2 mRNA and thus activating the apoptotic signal. CONCLUSIONS This study demonstrated a novel and critical role of LINC00173. It was transcriptionally repressed by DDP-activated PI3K/AKT/c-Myc signal in LUAD, promoting DDP-acquired chemotherapeutic resistance by regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, which led to apoptotic signal reduction. These data were not consistent with the previously described role of LINC00173 in SCLC or LUSC, which suggested that LINC00173 could play fine-tuned DDP resistance roles in different pathological subtypes of lung cancer. This study demonstrated that the diminished expression of LINC00173 might serve as an indicator of DDP-acquired resistance in LUAD.
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Affiliation(s)
- Xingyu Tao
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Yang Li
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Songqing Fan
- grid.452708.c0000 0004 1803 0208The Second Xiangya Hospital of Central South University, Changsha, 410008 China
| | - Liyang Wu
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Jianyang Xin
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Yun Su
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Xiaoyang Xian
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Yingying Huang
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Rongquan Huang
- grid.410737.60000 0000 8653 1072Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436 China
| | - Weiyi Fang
- grid.284723.80000 0000 8877 7471Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515 China ,grid.284723.80000 0000 8877 7471Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315 China
| | - Zhen Liu
- grid.284723.80000 0000 8877 7471Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315 China ,grid.410737.60000 0000 8653 1072Department of Pathology, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436 China
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Luo ZD, Wang YF, Zhao YX, Yu LC, Li T, Fan YJ, Zeng SJ, Zhang YL, Zhang Y, Zhang X. Emerging roles of non-coding RNAs in colorectal cancer oxaliplatin resistance and liquid biopsy potential. World J Gastroenterol 2023; 29:1-18. [PMID: 36683709 PMCID: PMC9850945 DOI: 10.3748/wjg.v29.i1.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/11/2022] [Accepted: 11/04/2022] [Indexed: 01/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with the annual incidence and mortality increasing consistently. Oxaliplatin-based chemotherapy is a preferred therapeutic regimen for patients with advanced CRC. However, most patients will inevitably develop resistance to oxaliplatin. Many studies have reported that non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs, are extensively involved in cancer progression. Moreover, emerging evidence has revealed that ncRNAs mediate chemoresistance to oxaliplatin by transcriptional and post-transcriptional regulation, and by epigenetic modification. In this review, we summarize the mechanisms by which ncRNAs regulate the initiation and development of CRC chemoresistance to oxaliplatin. Furthermore, we investigate the clinical application of ncRNAs as promising biomarkers for liquid CRC biopsy. This review provides new insights into overcoming oxaliplatin resistance in CRC by targeting ncRNAs.
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Affiliation(s)
- Zheng-Dong Luo
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yi-Feng Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yu-Xiao Zhao
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Long-Chen Yu
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Tian Li
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Ying-Jing Fan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Shun-Jie Zeng
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Yan-Li Zhang
- Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan 250012, Shandong Province, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan 250012, Shandong Province, China
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Li F, Tan B, Chen Z, Zhao Q, Li S, Ding P, Liu C, Wang X, Li X, Li Y. Long non-coding RNA CNALPTC1 promotes gastric cancer progression by regulating the miR-6788-5p/PAK1 pathway. J Gastrointest Oncol 2022; 13:2809-2822. [PMID: 36636079 PMCID: PMC9830357 DOI: 10.21037/jgo-22-1069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Background Gastric cancer (GC) is a globally prevalent gastrointestinal tumor. Long non-coding RNAs (lncRNAs) are a new type of transcript which has become a hotspot of current research; however, the function of most lncRNAs in the advancement of GC is still not clear. The focus of this research was to elucidate the role and expression of lncRNA CNALPTC1 in GC. Methods In GC cells and tissues, the detection of CNALPTC1 expression was carried out using quantitative real-time polymerase chain reaction (qRT-PCR), and the link between its expression and clinicopathological features was investigated. The impacts of inhibition and upregulation of CNALPTC1 on the physiological behavior of GC cells were observed. Furthermore, through bioinformatics analysis and prediction of microRNA (miRNA) targeted to CNALPTC1 and target genes interacting with miRNA, the effects on invasion, proliferation, and migration of GC cells were investigated. Results The elevated expression level of CNALPTC1 was observed in GC tissues and cell lines. The in vitro analysis indicated that gene silencing of CNALPTC1 resulted in inhibition, whereas upregulation of CNALPTC1 resulted in the promotion of invasion, proliferation, and migration of GC cells, respectively. In addition, we observed that CNALPTC1 functions as a molecular sponge for miR-6788-5p, and the level of expression of CNALPTC1 exhibited a negative correlation with miR-6788-5p. Moreover, it was revealed that the miR-6788-5p's direct target was PAK1, which could reverse the inhibitory function of miR-6788-5p. Conclusions Our research revealed that the CNALPTC1 promotes GC development by negatively regulating the miR-6788-5p/PAK1 pathway. GC therapy may be improved by conducting targeted studies of the CNALPTC1/miR-6788-5p/PAK1 axis.
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Affiliation(s)
- Fang Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bibo Tan
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zihao Chen
- Department of Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qun Zhao
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shi Li
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Pingan Ding
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chang Liu
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Wang
- Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaoya Li
- Department of Scientific Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Mirzaei S, Paskeh MDA, Entezari M, Mirmazloomi SR, Hassanpoor A, Aboutalebi M, Rezaei S, Hejazi ES, Kakavand A, Heidari H, Salimimoghadam S, Taheriazam A, Hashemi M, Samarghandian S. SOX2 function in cancers: Association with growth, invasion, stemness and therapy response. Biomed Pharmacother 2022; 156:113860. [DOI: 10.1016/j.biopha.2022.113860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/30/2022] [Accepted: 10/08/2022] [Indexed: 11/29/2022] Open
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LncRNA HOXA-AS2 Promotes Temozolomide Resistance in Glioblastoma by Regulated miR-302a-3p/IGF1 Axis. Genet Res (Camb) 2022; 2022:3941952. [PMID: 36479381 PMCID: PMC9705095 DOI: 10.1155/2022/3941952] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/23/2022] Open
Abstract
Background Glioblastoma (GBM) is a highly prevalent brain tumor characterized by high rates of morbidity, recurrence, and mortality. While temozolomide (TMZ) is commonly used as a first-line treatment for this cancer, the emergence of TMZ resistance limits its utility. The long noncoding RNA HOXA-AS2 reportedly drives GBM progression, but whether it can influence therapeutic resistance to TMZ has yet to be established. Methods HOXA-AS2 expression was analyzed in TMZ-resistant and sensitive GBM tissue samples and cell lines by qPCR. A siRNA-based approach was used to knock down HOXA-AS2 in GBM cells, after which TMZ resistance was tested. Bioinformatics approaches were used to predict miRNA binding targets of HOXA-AS2, after which a series of luciferase reporter assay and rescue experiments with appropriate miRNA inhibitor/mimic constructs were performed to validate these predictions and to clarify the ability of HOXA-AS2 to regulate chemoresistant activity. Results TMZ-resistant GBM patients and cell lines exhibited increased HOXA-AS2 expression that was correlated with worse overall survival. Knocking down HOXA-AS2 increased the sensitivity of resistant GBM cells to TMZ. miR-302a-3p was identified as a HOXA-AS2 target confirmed through luciferase reporter assays and rescue experiments, and IGF1 was further identified as a confirmed miR-302a-3p target. In addition, HOXA-AS2 knockdown resulted in a corresponding drop in IGF1 expression consistent with indirect regulation mediated by miR-302a-3p. Conclusion In summary, these results highlight the role of HOXA-AS2 as a driver of TMZ resistance in GBM through its ability to regulate the miR-302a-3p/IGF1 signaling axis, highlighting this pathway as a promising target for the diagnosis, therapeutic sensitization, and/or treatment of affected patients.
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Nayak A, Warrier NM, Kumar P. Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems. Stem Cell Rev Rep 2022; 18:2209-2233. [PMID: 35876959 PMCID: PMC9489588 DOI: 10.1007/s12015-022-10426-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2022] [Indexed: 11/25/2022]
Abstract
The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates-nanocarriers (NCs) especially-have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Central role of CSCs in regulation of cellular components within the TME.
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Affiliation(s)
- Aadya Nayak
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Noncoding RNAs: Regulating the crosstalk between tumor-associated macrophages and gastrointestinal cancer. Biomed Pharmacother 2022; 153:113370. [DOI: 10.1016/j.biopha.2022.113370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 01/19/2023] Open
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Wang D, Zhang P, Liu Z, Xing Y, Xiao Y. NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2. Cancers (Basel) 2022; 14:3782. [PMID: 35954445 PMCID: PMC9367313 DOI: 10.3390/cancers14153782] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/22/2022] [Accepted: 07/27/2022] [Indexed: 11/16/2022] Open
Abstract
Bladder cancer is one of the most prevalent kinds of cancer worldwide, and resistance to gemcitabine is a major problem for patients. The pathogenesis of bladder cancer and mechanism of resistance to chemotherapy remain to be explored. Through bioinformatics analysis, we first found that NXPH4 was independently related to the prognosis of patients with bladder cancer. Through wound healing assays, transwell invasion assays, and plate clone formation assays, we found that NXPH4 promoted the proliferation, migration, and invasion of bladder cancer cells. The induced gemcitabine resistance cell line also showed a higher expression of NXPH4. A glycolytic activity assay demonstrated that the expression of NXPH4 was positively related to glycolysis. A higher level of reactive oxygen species caused by enhanced levels of NXPH4 was found in gemcitabine-resistant cell lines. NDUFA4L2, glycolysis, and reactive oxygen species were shown to be essential for NXPH4-regulated functions through rescue assays in cell lines. The roles of NXPH4-regulated glycolysis, gemcitabine resistance, and NDUFA4L2 were validated in vivo as well. Our results imply that NXPH4 contributes to the proliferation, migration, and invasion of bladder cancer by maintaining the stability of NDUFA4L2 and consequently activating reactive oxygen species and glycolysis.
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Affiliation(s)
- Decai Wang
- Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (D.W.); (P.Z.)
| | - Pu Zhang
- Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (D.W.); (P.Z.)
| | - Zijian Liu
- Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Yifei Xing
- Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (D.W.); (P.Z.)
| | - Yajun Xiao
- Department of Urology Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (D.W.); (P.Z.)
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Yan S, Wang S, Wang X, Dai W, Chu J, Cheng M, Guo Z, Xu D. Emerging role of non-coding RNAs in glucose metabolic reprogramming and chemoresistance in colorectal cancer. Front Oncol 2022; 12:954329. [PMID: 35978828 PMCID: PMC9376248 DOI: 10.3389/fonc.2022.954329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/11/2022] [Indexed: 11/28/2022] Open
Abstract
Metabolic reprogramming plays a critical role in colorectal cancer (CRC). It contributes to CRC by shaping metabolic phenotypes and causing uncontrolled proliferation of CRC cells. Glucose metabolic reprogramming is common in carcinogenesis and cancer progression. Growing evidence has implicated the modifying effects of non-coding RNAs (ncRNAs) in glucose metabolic reprogramming and chemoresistance in CRC. In this review, we have summarized currently published studies investigating the role of ncRNAs in glucose metabolic alterations and chemoresistance in CRC. Elucidating the interplay between ncRNAs and glucose metabolic reprogramming provides insight into exploring novel biomarkers for the diagnosis and prognosis prediction of CRC.
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Affiliation(s)
- Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Shufeng Wang
- Medical Experimental Training Center, Weifang Medical University, Weifang, China
| | - Xinyi Wang
- Clinical Medicine of Basic Medical School, Shandong First Medical University, Jinan, China
| | - Wenqing Dai
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Jinjin Chu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
| | - Min Cheng
- Department of Physiology, Weifang Medical University, Weifang, China
| | - Zhiliang Guo
- Department of Spine Surgery, The 80th Group Army Hospital of Chinese People’s Liberation Army (PLA), Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
| | - Donghua Xu
- Central Laboratory of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Weifang, China
- *Correspondence: Zhiliang Guo, ; Donghua Xu,
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Yin X, Lin H, Lin L, Miao L, He J, Zhuo Z. LncRNAs and CircRNAs in cancer. MedComm (Beijing) 2022; 3:e141. [PMID: 35592755 PMCID: PMC9099016 DOI: 10.1002/mco2.141] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Xin Yin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
- College of Pharmacy Jinan University Guangzhou Guangdong China
| | - Huiran Lin
- Faculty of Medicine Macau University of Science and Technology Macau China
| | - Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong China
- Laboratory Animal Center, School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
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