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Wang XL, Zhang L, Shang Q. Circular RNA hsa_circRNA_101996 modulates gastric cancer cell proliferation and apoptosis through the miR-577/HMGN5 axis. World J Gastrointest Oncol 2025; 17:105933. [DOI: 10.4251/wjgo.v17.i5.105933] [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: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) are critical regulators in tumorigenesis, functioning as microRNA sponges or protein decoys. Although numerous circRNAs have been implicated in gastric cancer progression, the role of hsa_circRNA_101996 remains unclear. This study hypothesizes that hsa_circRNA_101996 promotes gastric cancer cell proliferation and apoptosis via the microRNA-577 (miR-577)/high mobility group nucleosome binding domain 5 (HMGN5) axis.
AIM To investigate the role of hsa_circRNA_101996 in gastric cancer proliferation and apoptosis through the miR-577/HMGN5 axis.
METHODS Forty-one paired gastric cancer tissues and adjacent non-cancerous tissues were analyzed. Differential circRNA expression was identified using GSE83521 and GSE89143 datasets. miR-577 and HMGN5 were predicted via CircInteractome and TargetScan. Functional experiments (MTT, colony formation, Western blot) and dual-luciferase reporter assays were performed in gastric cancer cell lines (OCUM-1, HSC-39). In vivo tumorigenesis was validated in nude mice. Statistical analysis included Student’s t-test and one-way ANOVA (P < 0.05).
RESULTS Hsa_circRNA_101996 was significantly upregulated in gastric cancer tissues and cell lines compared to adjacent non-cancerous tissues (P < 0.05). Dual-luciferase reporter assays validated the interactions among hsa_circRNA_101996, miR-577, and HMGN5. In vitro, gastric cancer cells overexpressing hsa_circRNA_101996 showed significantly increased proliferation and decreased apoptosis compared to controls (P < 0.05). Cells transfected with miR-577 mimics exhibited reduced proliferation and increased apoptosis (P < 0.05). Co-transfection with hsa_circRNA_101996 or HMGN5 reversed the effects of miR-577 mimics. In vivo, hsa_circRNA_101996-overexpressing tumors showed increased volume and HMGN5 expression (P < 0.05).
CONCLUSION Hsa_circRNA_101996 promotes gastric cancer progression by sponging miR-577 to upregulate HMGN5, suggesting a novel therapeutic target for gastric cancer.
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Affiliation(s)
- Xiao-Lei Wang
- Department of General Surgery, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Lin Zhang
- Department of Oncology, The First People's Hospital of Changshu, Suzhou 215501, Jiangsu Province, China
| | - Qing Shang
- Department of General Surgery, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
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Zhu J, Jiang C, Wang F, Tao MY, Wang HX, Sun Y, Hui HX. NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer. Curr Med Sci 2025; 45:264-279. [PMID: 40029499 DOI: 10.1007/s11596-025-00013-7] [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: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 03/05/2025]
Abstract
OBJECTIVE Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are known as major sources of reactive oxygen species (ROS), yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear. This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression METHODS: We analyzed transcriptomic and survival data from The Cancer Genome Atlas (TCGA) for NOXs across 22 types of solid tumors. A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells (CRCs). Techniques such as CRISPR-knockout cell lines, 1,2-13C-glucose tracing, PI staining, BrdU assays, and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs. RESULTS NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data. CRISPR screening highlighted its essential role in CRC survival, with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation. The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase (G6PD) was found to enhance the pentose phosphate pathway (PPP), facilitating ROS clearance and protecting CRCs against ferroptosis. CONCLUSIONS This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer. The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.
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Affiliation(s)
- Jing Zhu
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Chao Jiang
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Fan Wang
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Ming-Yue Tao
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Hai-Xiao Wang
- Department of General Surgery, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Yuan Sun
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Hong-Xia Hui
- Department of Medical Oncology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China.
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Yang K, Zhang X, Long F, Dai J. AKR1B1 Inhibits Ferroptosis and Promotes Gastric Cancer Progression via Interacting With STAT3 to Activate SLC7A11. Cell Biol Int 2025; 49:374-383. [PMID: 39911124 DOI: 10.1002/cbin.12275] [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: 08/19/2024] [Revised: 12/18/2024] [Accepted: 12/26/2024] [Indexed: 02/07/2025]
Abstract
Gastric cancer (GC) is a frequently diagnosed malignant tumor in clinical settings; however, the mechanisms underlying its tumorigenesis remain inadequately understood. In this study, we identified significantly elevated expression levels of AKR1B1 in GC tissues through quantitative polymerase chain reaction (qPCR) and western blotting assays. Furthermore, a negative correlation was established between patient survival probability and AKR1B1 expression levels. Functionally, our experiments, including colony formation, transwell migration, and xenograft assays, demonstrated that the depletion of AKR1B1 inhibited the proliferation and progression of GC cells both in vivo and in vitro. Additionally, the assessment of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and mitochondrial morphology confirmed that AKR1B1 depletion induces ferroptosis. Mechanistically, we found that AKR1B1 interacts with STAT3, which subsequently activates SLC7A11. Notably, the ferroptosis induced by AKR1B1 depletion could be reversed by the overexpression of SLC7A11, thereby substantiating these interactions. In conclusion, our findings identify AKR1B1 as a novel oncogene in GC and elucidate the mechanism involving the AKR1B1-STAT3-SLC7A11 pathway and ferroptosis, providing new insights for potential therapeutic strategies in the treatment of GC.
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Affiliation(s)
- Kaiyan Yang
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, China
| | - Xin Zhang
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, China
| | - Fei Long
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, China
| | - Jing Dai
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan, China
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Wang S, Wu C, Wang J, Yuan F, Hou Y, Cao T, Xu L, Qian L, Xia Y, Xu L, Zeng A, Wang X, Wang L, Huang X. Hsa_circ_0002301 inhibits ferroptosis in gastric cancer by encoding the de novo protein HECTD1-463aa. J Transl Med 2025; 23:250. [PMID: 40022084 PMCID: PMC11871676 DOI: 10.1186/s12967-025-06226-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 02/11/2025] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND CircRNAs are closely related to ferroptosis in gastric cancer cells; however, the mechanism by which circRNAs regulate ferroptosis in gastric carcinogenesis remains unknown. CircRNA-encoded novel peptides are functional products translated from the open reading frames (ORFs) within circular RNAs, demonstrating that circRNAs not only serve as non-coding regulators but also have the capacity to encode biologically active peptides. Compared with noncancerous cells, cancer cells have greater iron requirements, and ferroptosis occurs in response to radiotherapy, chemotherapy, and immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the shortcomings of conventional cancer therapy. METHODS A mouse model of ferroptosis in gastric cancer was constructed, and a bioinformatics analysis was performed to analyze and characterize the circRNAs involved in ferroptosis in gastric cancer. The inhibitory effect of hsa_circ_0002301 on ferroptosis in tumors was confirmed both in vitro and in vivo. The presence and expression of HECTD1-463aa were verified using mass spectrometry, protein blotting, and immunofluorescence staining. The molecular mechanism of hsa_circ_0002301 was investigated using mass spectrometry and immunoprecipitation. RESULTS We designed and synthesized antibodies specific for the small protein HECTD1-463aa encoded by hsa_circ_0002301 to verify its presence and purified HECTD1-463aa by constructing hsa_circ_0002301 overexpression vectors with FLAG tags and used liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to detect the characterized peptides. In addition, HECTD1 binding to HECTD1-463aa was identified by immunoprecipitation (Co-IP) and mass spectrometry. We found that HECTD1-463aa inhibited HECTD1-mediated GPX4 ubiquitination by binding to HECTD1, an important regulator of cell death in ferroptotic cancer cells. CONCLUSIONS hsa_circ_0002301 competitively inhibits the degradation of the GPX4 protein by HECTD1 through the encoded proteins HECTD1-463aa and HECTD1 to affect the ferroptosis level in gastric cancer cells.
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Affiliation(s)
- Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Chengwei Wu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Jiawei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Feng Yuan
- Department of Ultrasound, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yinfen Hou
- Department of Medical Examination Center, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Tingting Cao
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Lishuai Xu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Long Qian
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China
| | - Ailiang Zeng
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Xiaoming Wang
- Department of Hepato-Biliary-Pancreatic Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China
| | - Luman Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Xiaoxu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui, Anhui, 241001, China.
- Anhui Province Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wuhu, Anhui, China.
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Pan Y, Liu S, Shu G, Chen M, Fu L, Chen C, Chen Y, Zhuang Q, Xue D, He X. STX17-DT facilitates axitinib resistance in renal cell carcinoma by inhibiting mitochondrial ROS accumulation and ferroptosis. Cell Death Dis 2025; 16:125. [PMID: 39988631 PMCID: PMC11847927 DOI: 10.1038/s41419-025-07456-9] [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: 10/07/2024] [Revised: 02/08/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
Axitinib resistance remains a serious challenge in the treatment of advanced renal cell carcinoma (RCC), and the underlying mechanisms are not fully understood. Here, we constructed an in vivo axitinib-resistant RCC model and identified the long non-coding RNA STX17-DT as a driver of therapy resistance in RCC. The expression of STX17-DT was significantly elevated in axitinib-resistant RCC cells and correlated with poorer prognosis in RCC patients. Elevated levels of STX17-DT contributed to the development of resistance to axitinib both in vitro and in vivo. Mechanistically, STX17-DT modulated the stability of IFI6 mRNA by recruiting and binding to hnRNPA1, leading to decreased accumulation of mitochondrial reactive oxygen species (ROS) and attenuated ferroptosis. Meanwhile, STX17-DT was packaged into extracellular vesicles through hnRNPA1, thus transmitting axitinib resistance to other cells. Compared with axitinib monotherapy, combined treatment of axitinib and STX17-DT-targeted in vivo siRNA demonstrated enhanced therapeutic efficacy. These findings indicate a novel molecular mechanism of axitinib resistance in RCC and suggest that STX17-DT may serve as a prognostic indicator and potential therapeutic target to overcome resistance to targeted therapy.
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Affiliation(s)
- Yihui Pan
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Shuang Liu
- Department of Oncology, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Guannan Shu
- Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, Guangdong, China
- 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
| | - Minyu Chen
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liangmin Fu
- Department of Urology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Uro-Oncology Institute of Central South University, Changsha, Hunan, China
| | - Cheng Chen
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yimeng Chen
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qianfeng Zhuang
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Xiaozhou He
- Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, China.
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Zhang Y, Li J. Study on hsa_circ_101209 in Plasma of Pregnant Women with Deep Venous Thrombosis. Int J Gen Med 2025; 18:209-219. [PMID: 39834914 PMCID: PMC11742753 DOI: 10.2147/ijgm.s477830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 11/12/2024] [Indexed: 01/22/2025] Open
Abstract
Background This study analyzed the expression and diagnostic value of hsa_circ_101209 in plasma of pregnant women with in deep vein thrombosis (DVT). Methods By circRNA microarray detection and GO/KEGG analysis, hsa_circ_14797 targeting miRNA-mRNA network was predicted. Sixty women with DVT were selected as the DVT group, and 60 women without DVT as the non-DVT group. hsa_circ_14797 in plasma was detected, as well as D-dimer (D-D) concentration and P-selectin expression. Target genes that may be regulated by hsa_circ_14797 were predicted, and GO analysis and KEGG pathway enrichment analysis were performed. Results hsa_circ_14797 was highly expressed in DVT. hsa_circ_14797 in plasma of DVT patients was positively correlated with D-D (r = 0.358, P = 0.001). The AUC of plasma hsa_circ_14797, D-D, and P-selectin for maternal DVT diagnosis were 0.787 (95% CI: 0.710-0.864), 0.882 (95% CI: 0.821-0.943), and 0.825 (95% CI: 0.754-0.895), respectively. The AUC of hsa_circ_14797 combined with D-D was 0.886 (95% CI: 0.828-0.944). The AUC of hsa_circ_14797 combined with P-selectin was 0.904 (95% CI: 0.853-0.954). The AUC of P-selectin combined with D-D was 0.935 (95% CI: 0.893-0.978). The AUC of hsa_circ_14797 combined with D-D and P-selectin was 0.953 (95% CI: 0.920-0.986). The functions of hsa_circ_14797 included the biological processes of angiogenesis, vascular development, and vascular morphology. The enrichment pathways included PI3K-Akt pathway, TGF-β pathway, and cytokine-cytokine receptor interaction. Conclusion hsa_circ_14797, D-D, and P-selectin in plasma of DVT pregnant patients are increased, and hsa_circ_14797 in plasma is positively correlated with D-D. hsa_circ_14797 combined with D-D and P-selectin can improve the accuracy of diagnosis of DVT and contribute to the early diagnosis of DVT.
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Affiliation(s)
- Yuhong Zhang
- Center for Obstetrics and Reproductive Medicine, The Affiliated Hospital of Yunnan University, Kunming City, Yunnan Province, 650032, People’s Republic of China
| | - Jun Li
- Center for Obstetrics and Reproductive Medicine, The Affiliated Hospital of Yunnan University, Kunming City, Yunnan Province, 650032, People’s Republic of China
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Zhang J, Luo X, Guo C, Dai Z, Tang X, Zhang F, Jiao Q, Lin S, Zou L, Zhang Z, Lv XB. LncRNA GClnc1 promotes osteosarcoma progression by stabilizing NONO and blocking FBXW7-mediated ubiquitination. BMC Cancer 2024; 24:1375. [PMID: 39523321 PMCID: PMC11552323 DOI: 10.1186/s12885-024-13138-0] [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: 07/24/2023] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) plays a vital role in the occurrence and development of varieties of tumors. Previous studies have shown that lncRNA GClnc1 is highly expressed in osteosarcoma (OS). However, the mechanism of lncRNA GClnc1 in osteosarcoma has not been fully elucidated. In this study, we investigated the biological roles of lncRNA GClnc1 in osteosarcoma and unveiled its underlying mechanisms. METHODS The expression of lncRNA GClnc1 in OS cells was detected by real-time quantitative PCR (qRT-PCR). The functional roles of lncRNA GClnc1 were examined by CCK8, trans-well, scratch wound healing assay, colony formation, and apoptosis assays in osteosarcoma cells upon silencing or overexpressing GClnc1. Western blot analysis, qRT-PCR, and RNA co-immunoprecipitation (RIP) assays were used to detect the interaction between lncRNA GClnc1 and NONO. RESULTS The expression of lncRNA GClnc1 was up-regulated in osteosarcoma cell lines. Knockdown of lncRNA GClnc1 suppressed the cell growth, migration, and invasion of OS cells, whereas the over-expression of GClnc1 improved the proliferation, migration, and invasion of OS cells. Mechanistically, we identified that lncRNA GClnc1 regulates the stability of NONO by blocking FBXW7-mediated ubiquitination degradation. Additionally, overexpression of NONO can reverse GClnc1 silencing exerted suppression of the cell proliferation, migration, and invasion, and vice versa. CONCLUSIONS Our study elucidated that lncRNA GClnc1 participates in the progression of OS by regulating the NONO signal pathway. Targeting GClnc1 provides a potential target for future clinical treatment of OS.
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Affiliation(s)
- Jiongfeng Zhang
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China
| | - Xiaohui Luo
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China
| | - Chong Guo
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China
| | - Zhengzai Dai
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
| | - Xiaofeng Tang
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China
| | - Feifei Zhang
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China
| | - Quanhui Jiao
- College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Shifan Lin
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
| | - Le Zou
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China
| | - Zhiping Zhang
- Jiangxi Key Laboratory of Oncology, The Central Lab of The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, North 128 Xiangshan Road, Nanchang, 330008, China.
| | - Xiao-Bin Lv
- Department of Orthopedics, Nanchang Key Laboratory of Orthopaedics, The First Hospital of Nanchang, The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330008, China.
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Xie J, Liang X, Xie F, Huang C, Lin Z, Xie S, Yang F, Zheng F, Geng L, Xu W, Gong S, Xiang L. Rabeprazole suppressed gastric intestinal metaplasia through activation of GPX4-mediated ferroptosis. Front Pharmacol 2024; 15:1409001. [PMID: 39575386 PMCID: PMC11578692 DOI: 10.3389/fphar.2024.1409001] [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: 03/29/2024] [Accepted: 09/20/2024] [Indexed: 11/24/2024] Open
Abstract
Background Gastric intestinal metaplasia is a common pathological feature in patients with Helicobacter pylori (H. pylori) infection. Rabeprazole was widely used as the first-line regimen for H. pylori infectious treatment. The objective of this study is to explore the mechanism of rabeprazole in gastric intestinal metaplasia treatment. Methods Real-time PCR, Western blotting (WB) and ROS analysis were conducted to confirm that rabeprazole could induce ferroptosis to suppress gastric intestinal metaplasia. Cellular fraction, luciferase and chromatin immunoprecipitation (ChIP) were used to identify the mechanism underlying rabeprazole modulated ferroptosis. Results Herein, we found rabeprazole treatment led to inhibit CDX2 and MUC2 expression, alleviating gastric intestinal metaplasia, which was attributed to enhanced ferroptosis characterized by decreased GPX4 expression. Inhibition of ferroptosis by ferrostatin-1 (Fer-1) could reverse decreased CDX2 and MUC2 expression caused by rabeprazole. Mechanically, Rabeprazole could inhibit CREB phosphorylation and nuclear translocation, which further decreased the binding of CREB to GPX4 promoter, reducing GPX4 transactivity. Moreover, endogenous PKA interacted with CREB, and this interaction was drastically destroyed in response to rabeprazole treatment. Most importantly, enhanced ferroptosis was observed in H. pylori-infected gastric intestinal metaplasia in comparison to HC control. Conclusion These findings suggested that rabeprazole induced ferroptosis to reduce CDX2 expression in gastric epithelial cells through PKA/CREB cascade signaling, implying that targeting ferroptosis could be a promising strategy in improving gastric intestinal metaplasia during H. pylori-infected patients.
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Affiliation(s)
- Jing Xie
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Xinhua Liang
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fangfang Xie
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Canxin Huang
- School of Second Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zijun Lin
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shuping Xie
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fangying Yang
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fengfeng Zheng
- Department of Infectious Diseases, The Affiliate Hospital of Putian University, Putian, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Li Xiang
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
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9
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Muluh TA, Fu Q, Ai X, Wang C, Chen W, Zheng X, Wang W, Wang M, Shu XS, Ying Y. Targeting Ferroptosis as an Advance Strategy in Cancer Therapy. Antioxid Redox Signal 2024; 41:616-636. [PMID: 38959114 DOI: 10.1089/ars.2024.0608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
Significance: This study innovates by systematically integrating the molecular mechanisms of iron death and its application in cancer therapy. By deeply analyzing the interaction between iron death and the tumor microenvironment, the study provides a new theoretical basis for cancer treatment and directions for developing more effective treatment strategies. In addition, the study points to critical issues and barriers that need to be addressed in future research, providing valuable insights into the use of iron death in clinical translation. Recent Advances: These findings are expected to drive further advances in cancer treatment, bringing patients more treatment options and hope. Through this paper, we see the great potential of iron death in cancer treatment and look forward to more research results being translated into clinical applications in the future to contribute to the fight against cancer. Critical Issues: In today's society, cancer is still one of the major diseases threatening human health. Despite advances in existing treatments, cancer recurrence and drug resistance remain a severe problem. These problems increase the difficulty of treatment and bring a substantial physical and mental burden to patients. Therefore, finding new treatment strategies to overcome these challenges has become significant. Future Directions: The study delved into the molecular basis of iron death in tumor biology. It proposed a conceptual framework to account for the interaction of iron death with the tumor immune microenvironment, guide treatment selection, predict efficacy, explore combination therapies, and identify new therapeutic targets to overcome cancer resistance to standard treatments, peeving a path for future research and clinical translation of ferroptosis as a potential strategy in cancer therapy. Antioxid. Redox Signal. 41, 616-636. [Figure: see text].
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Affiliation(s)
- Tobias Achu Muluh
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Qianqian Fu
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Xiaojiao Ai
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Changfeng Wang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Wei Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Xiangyi Zheng
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Wei Wang
- Shanghai Waker Bioscience Co., Ltd., Shanghai, China
| | - Maolin Wang
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Xing-Sheng Shu
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
- Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Ying Ying
- Shenzhen University Medical School, Shenzhen University, Shenzhen, China
- Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, China
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10
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Bhat AA, Kukreti N, Afzal M, Goyal A, Thapa R, Ali H, Shahwan M, Almalki WH, Kazmi I, Alzarea SI, Singh SK, Dua K, Gupta G. Ferroptosis and circular RNAs: new horizons in cancer therapy. EXCLI JOURNAL 2024; 23:570-599. [PMID: 38887390 PMCID: PMC11180955 DOI: 10.17179/excli2024-7005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/09/2024] [Indexed: 06/20/2024]
Abstract
Cancer poses intricate challenges to treatment due to its complexity and diversity. Ferroptosis and circular RNAs (circRNAs) are emerging as innovative therapeutic avenues amid the evolving landscape of cancer therapy. Extensive investigations into circRNAs reveal their diverse roles, ranging from molecular regulators to pivotal influencers of ferroptosis in cancer cell lines. The results underscore the significance of circRNAs in modulating molecular pathways that impact crucial aspects of cancer development, including cell survival, proliferation, and metastasis. A detailed analysis delineates these pathways, shedding light on the molecular mechanisms through which circRNAs influence ferroptosis. Building upon recent experimental findings, the study evaluates the therapeutic potential of targeting circRNAs to induce ferroptosis. By identifying specific circRNAs associated with the etiology of cancer, this analysis paves the way for the development of targeted therapeutics that exploit vulnerabilities in cancer cells. This review consolidates the existing understanding of ferroptosis and circRNAs, emphasizing their role in cancer therapy and providing impetus for ongoing research in this dynamic field. See also the graphical abstract(Fig. 1).
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Affiliation(s)
- Asif Ahmad Bhat
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, U. P., India
| | - Riya Thapa
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
| | - Haider Ali
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Moyad Shahwan
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, 346, United Arab Emirates
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, Ajman, 346, United Arab Emirates
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Sami I. Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Al-Jouf, Saudi Arabia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India
- Faculty of Health, Australian Research Center in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- School of Medical and Life Sciences, Sunway University, Sunway, Malaysia
| | - Kamal Dua
- Faculty of Health, Australian Research Center in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- Discipline of Pharmacy, Graduate School of Health, University of Technology, Sydney, Ultimo-NSW 2007, Australia
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, Ajman, 346, United Arab Emirates
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11
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Zhao W, Yao Z, Cao J, Liu Y, Zhu L, Mao B, Cui F, Shao S. Helicobacter pylori upregulates circPGD and promotes development of gastric cancer. J Cancer Res Clin Oncol 2024; 150:104. [PMID: 38407616 PMCID: PMC10896836 DOI: 10.1007/s00432-023-05537-w] [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: 10/02/2023] [Accepted: 11/29/2023] [Indexed: 02/27/2024]
Abstract
PURPOSE Helicobacter pylori (H. pylori) has unique biochemical traits and pathogenic mechanisms, which make it a substantial cause of gastrointestinal cancers. Circular RNAs (circRNAs) have concurrently been identified as an important participating factor in the pathophysiology of several different cancers. However, the underlying processes and putative interactions between H. pylori and circRNAs have received very little attention. To address this issue, we explored the interaction between H. pylori and circRNAs to investigate how they might jointly contribute to the occurrence and development of gastric cancer. METHODS Changes in circPGD expression in H. pylori were detected using qRT-PCR. Cell proliferation and migration changes were assayed by colony formation, the CCK-8 assay and the transwell assay. Apoptosis was measured by flow cytometry. Western blot was conducted to detect changes in cell migration, apoptosis, proliferation and inflammation-associated proteins. QRT-PCR was used to measure changes in circPGD and inflammation-associated factors. RESULTS We found that H. pylori induced increased circPGD expression in infected human cells and facilitated gastric cancer progression in three ways by promoting cell proliferation and migration, enhancing the inflammatory response, and inhibiting apoptosis. CONCLUSIONS CircPGD appears to play a role in H. pylori-related gastric cancer and may thus be a viable, novel target for therapeutic intervention.
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Affiliation(s)
- Wenjun Zhao
- The Affiliated Yixing Hospital of Jiangsu University, Wuxi, 214200, Jiangsu, China
- Urology Department, The Affiliated Taizhou Second People's Hospital of Yangzhou University, Taizhou, 225500, Jiangsu, China
| | - Zhendong Yao
- The Affiliated Yixing Hospital of Jiangsu University, Wuxi, 214200, Jiangsu, China
| | - Jia Cao
- School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200120, China
| | - Yun Liu
- Jiangsu University School of Medicine, Zhenjiang, 212013, Jiangsu, China
| | - Linqi Zhu
- Jiangsu University School of Medicine, Zhenjiang, 212013, Jiangsu, China
| | - Boneng Mao
- The Affiliated Yixing Hospital of Jiangsu University, Wuxi, 214200, Jiangsu, China.
| | - Feilun Cui
- Urology Department, The Affiliated Taizhou Second People's Hospital of Yangzhou University, Taizhou, 225500, Jiangsu, China.
| | - Shihe Shao
- Jiangsu University School of Medicine, Zhenjiang, 212013, Jiangsu, China.
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12
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Xiao P, Li C, Liu Y, Gao Y, Liang X, Liu C, Yang W. The role of metal ions in the occurrence, progression, drug resistance, and biological characteristics of gastric cancer. Front Pharmacol 2024; 15:1333543. [PMID: 38370477 PMCID: PMC10869614 DOI: 10.3389/fphar.2024.1333543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/22/2024] [Indexed: 02/20/2024] Open
Abstract
Metal ions exert pivotal functions within the human body, encompassing essential roles in upholding cell structure, gene expression regulation, and catalytic enzyme activity. Additionally, they significantly influence various pathways implicated in divergent mechanisms of cell death. Among the prevailing malignant tumors of the digestive tract worldwide, gastric cancer stands prominent, exhibiting persistent high mortality rates. A compelling body of evidence reveals conspicuous ion irregularities in tumor tissues, encompassing gastric cancer. Notably, metal ions have been observed to elicit distinct contributions to the progression, drug resistance, and biological attributes of gastric cancer. This review consolidates pertinent literature on the involvement of metal ions in the etiology and advancement of gastric cancer. Particular attention is directed towards metal ions, namely, Na, K, Mg, Ca, Fe, Cu, Zn, and Mn, elucidating their roles in the initiation and progression of gastric cancer, cellular demise processes, drug resistance phenomena, and therapeutic approaches.
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Affiliation(s)
- Pengtuo Xiao
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuanda Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yan Gao
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiaojing Liang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chang Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
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13
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Wang J, Jia Q, Jiang S, Lu W, Ning H. POU6F1 promotes ferroptosis by increasing lncRNA-CASC2 transcription to regulate SOCS2/SLC7A11 signaling in gastric cancer. Cell Biol Toxicol 2024; 40:3. [PMID: 38267746 PMCID: PMC10808632 DOI: 10.1007/s10565-024-09843-y] [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: 08/18/2023] [Accepted: 11/22/2023] [Indexed: 01/26/2024]
Abstract
OBJECTIVE This study investigated the effect and mechanism of POU6F1 and lncRNA-CASC2 on ferroptosis of gastric cancer (GC) cells. METHODS GC cells treated with erastin and RSL3 were detected for ferroptosis, reactive oxygen species (ROS) level, and cell viability. The expression levels of POU6F1, lncRNA-CASC2, SOCS2, and ferroptosis-related molecules (GPX4 and SLC7A11) were also measured. The regulations among POU6F1, lncRNA-CASC2, FMR1, SOCS2, and SLC7A11 were determined. Subcutaneous tumor models were established, in which the expressions of Ki-67, SOCS2, and GPX4 were detected by immunohistochemistry. RESULTS GC patients with decreased expressions of POU6F1 and lncRNA-CASC2 had lower survival rate. Overexpression of POU6F1 or lncRNA-CASC2 decreased cell proliferation and GSH levels in GC cells, in addition to increasing total iron, Fe2+, MDA, and ROS levels. POU6F1 directly binds to the lncRNA-CASC2 promoter to promote its transcription. LncRNA-CASC2 can target FMR1 and increase SOCS2 mRNA stability to promote SLC7A11 ubiquitination degradation and activate ferroptosis signaling. Knockdown of SOCS2 inhibited the ferroptosis sensitivity of GC cells and reversed the effects of POU6F1 and lncRNA-CASC2 overexpression on ferroptosis in GC cells. CONCLUSION Transcription factor POU6F1 binds directly to the lncRNA-CASC2 promoter to promote its expression, while upregulated lncRNA-CASC2 increases SOCS2 stability and expression by targeting FMR1, thereby inhibiting SLC7A11 signaling to promote ferroptosis in GC cells and inhibit GC progression.
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Affiliation(s)
- Jingyun Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou, Henan, 450000, People's Republic of China
| | - Qiaoyu Jia
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou, Henan, 450000, People's Republic of China
| | - Shuqin Jiang
- Department of Child Development and Behavior, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, People's Republic of China
| | - Wenquan Lu
- Department of Gastroenterology, The Second Affiliated Hospital of Zhengzhou University, No.2 JingBa Road, Jinshui District, Zhengzhou, Henan, 450014, People's Republic of China
| | - Hanbing Ning
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi District, Zhengzhou, Henan, 450000, People's Republic of China.
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14
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Li T, Yang Q, Liu Y, Jin Y, Song B, sun Q, Wei S, Wu J, Li X. Machine Learning Identify Ferroptosis-Related Genes as Potential Diagnostic Biomarkers for Gastric Intestinal Metaplasia. Technol Cancer Res Treat 2024; 23:15330338241272036. [PMID: 39169865 PMCID: PMC11342439 DOI: 10.1177/15330338241272036] [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: 04/22/2024] [Revised: 05/02/2024] [Accepted: 05/28/2028] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND Gastric intestinal metaplasia(GIM) is an independent risk factor for GC, however, its pathogenesis is still unclear. Ferroptosis is a new type of programmed cell death, which may be involved in the process of GIM. The purpose of this study was to analyze the expression of ferroptosis-related genes (FRGs) in GIM tissues and to explore the relationship between ferroptosis and GIM. METHOD The results of GIM tissue full transcriptome sequencing were downloaded from Gene Expression Omnibus(GEO) database. R software (V4.2.0) and R packages were used for screening and enrichment analysis of differentially expressed genes(DEGs). The key genes were screened by least absolute shrinkage and selection operator(LASSO) and support vector machine-recursive feature elimination(SVM-RFE) algorithm. Receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of key genes in GIM. Clinical samples were used to further validate hub genes. RESULTS A total of 12 differentially expressed ferroptosis-related genes (DEFRGs) were identified. Using two machine learning algorithms, GOT1, ALDH3A2, ACSF2 and SESN2 were identified as key genes. The area under ROC curve (AUC) of GOT1, ALDH3A2, ACSF2 and SESN2 in the training set were 0.906, 0.955, 0.899 and 0.962 respectively, and the AUC in the verification set were 0.776, 0.676, 0.773 and 0.880, respectively. Clinical samples verified the differential expression of GOT1, ACSF2, and SESN2 in GIM. CONCLUSION We found that there was a significant correlation between ferroptosis and GIM. GOT1, ACSF2 and SESN2 can be used as diagnostic markers to effectively identify GIM.
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Affiliation(s)
- Tingting Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qi Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yun Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yueping Jin
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Biao Song
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qin sun
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Siyuan Wei
- The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Jing Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Xuejun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
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15
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Dai ZT, Wu YL, Li XR, Liao XH. MKL-1 suppresses ferroptosis by activating system Xc- and increasing glutathione synthesis. Int J Biol Sci 2023; 19:4457-4475. [PMID: 37781038 PMCID: PMC10535709 DOI: 10.7150/ijbs.80666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 08/09/2023] [Indexed: 10/03/2023] Open
Abstract
Chemotherapy is a standard method in traditional treatment for gastric cancer. It is well known that the anti-tumor effects of chemotherapy are achieved mainly through the direct killing of cancer cells via apoptosis. However, chemotherapy often fails due to drug resistance. Therefore, non-apoptotic cell death induction by ferroptosis has recently been proposed as a new therapeutic modality to ablate cancer. In this study, we determined the role of MKL-1 in ferroptosis. In vitro and in vivo experiments showed that inhibition of MKL-1 expression significantly enhanced cell sensitivity to ferroptosis-inducing agents. It functions by targeting system Xc- to affect the synthesis of GSH in cells. Therefore, we developed an exosome-based therapeutic approach targeting MKL-1, which provides a novel insight into the treatment of gastric cancer.
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Affiliation(s)
- Zhou-Tong Dai
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Centre for Obstetrics and Gynaecology, Cancer Biology Research Centre (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Biology and Medicine, College of Life and Health Science, Wuhan University of Science and Technology, Wuhan, China
| | - Yong-Lin Wu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Rui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Science, Wuhan University of Science and Technology, Wuhan, China
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16
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Chen C, Du P, Zhang Z, Bao D. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress. Open Life Sci 2023; 18:20220514. [PMID: 36852400 PMCID: PMC9961966 DOI: 10.1515/biol-2022-0514] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/08/2022] [Accepted: 09/21/2022] [Indexed: 02/25/2023] Open
Abstract
Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identified as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-flurorouracil. However, 6-PGDH knockdown did not affect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro findings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy.
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Affiliation(s)
- Cheng Chen
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Sciences, Xiangyang441021, China,Institute of Oncology, Hubei University of Arts and Science, Xiangyang441021, China
| | - Pan Du
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Sciences, Xiangyang441021, China,Institute of Oncology, Hubei University of Arts and Science, Xiangyang441021, China
| | - Zhenguo Zhang
- Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Sciences, Xiangyang441021, China
| | - Di Bao
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Sciences, Xiangyang441021, China,Institute of Oncology, Hubei University of Arts and Science, Xiangyang441021, China
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17
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Song B, Li T, Zhang Y, Yang Q, Pei B, Liu Y, Wang J, Dong G, Sun Q, Fan S, Li X. Identification and verification of ferroptosis-related genes in gastric intestinal metaplasia. Front Genet 2023; 14:1152414. [PMID: 37144125 PMCID: PMC10151495 DOI: 10.3389/fgene.2023.1152414] [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: 01/27/2023] [Accepted: 04/05/2023] [Indexed: 05/06/2023] Open
Abstract
Background: Gastric intestinal metaplasia (IM) is the key link of gastric precancerous lesions. Ferroptosis is a novel form of programmed cell death. However, its impact on IM is unclear. The focus of this study is to identify and verify ferroptosis-related genes (FRGs) that may be involved in IM by bioinformatics analysis. Materials and methods: Differentially expressed genes (DEGs) were obtained from microarray dataset GSE60427 and GSE78523 downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed ferroptosis-related genes (DEFRGs) were obtained from overlapping genes of DEGs and FRGs got from FerrDb. DAVID database was used for functional enrichment analysis. Protein-protein interaction (PPI) analysis and Cytoscape software were used to screen hub gene. In addition, we built a receiver operating characteristic (ROC) curve and verified the relative mRNA expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the CIBERSORT algorithm was used to analyze the immune infiltration in IM. Results: First, a total of 17 DEFRGs were identified. Second, a gene module identified by Cytoscape software was considered as hub gene: PTGS2, HMOX1, IFNG, and NOS2. Third, ROC analysis showed that HMOX1 and NOS2 had good diagnostic characteristics. qRT-PCR experiments confirmed the differential expression of HMOX1 in IM and normal gastric tissues. Finally, immunoassay showed that the proportion of T cells regulatory (Tregs) and macrophages M0 in IM was relatively higher, while the proportion of T cells CD4 memory activated and dendritic cells activated was lower. Conclusion: We found significant associations between FRGs and IM, and HMOX1 may be diagnostic biomarkers and therapeutic targets for IM. These results may enhance our understanding of IM and may contribute to its treatment.
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Affiliation(s)
- Biao Song
- The Graduated School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Tingting Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yi Zhang
- The Graduated School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qi Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Bei Pei
- The Graduated School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yun Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Jieyu Wang
- The Graduated School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Gang Dong
- The Graduated School, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Qin Sun
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | | | - Xuejun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- *Correspondence: Xuejun Li,
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