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Hoshida T, Tsubaki M, Takeda T, Asano R, Choi IH, Takimoto K, Inukai A, Imano M, Tanabe K, Nagai N, Nishida S. Oxaliplatin and 5-fluorouracil promote epithelial-mesenchymal transition via activation of KRAS/ERK/NF-κB pathway in KRAS-mutated colon cancer cells. Mol Cell Biochem 2025; 480:2985-2999. [PMID: 39586908 DOI: 10.1007/s11010-024-05157-z] [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: 03/08/2024] [Accepted: 11/05/2024] [Indexed: 11/27/2024]
Abstract
Oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) are used to treat colon cancer; however, resistance contributes to poor prognosis. Epithelial-mesenchymal transition (EMT) has been induced in tumor tissues after administration of anticancer drugs and may be involved in drug resistance. We investigated the mechanism of EMT induction in colon cancer cells treated with 5-FU and L-OHP. We found that L-OHP and 5-FU at clinical steady-state concentrations induced EMT in LoVo and DLD-1 cells (KRAS G13D-mutated), but not in HT-29 and Caco-2 cells (KRAS wild type). L-OHP and 5-FU elevated vimentin, N-cadherin, Twist, Slug, and Snail and decreased E-cadherin expressions. Moreover, 5-FU- and L-OHP -induced EMT cells showed increased cell migration and decreased sensitivity to 5-FU and L-OHP. L-OHP and 5-FU treatment promoted KRAS, ERK1/2, and NF-κB activation. Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.
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Affiliation(s)
- Tadafumi Hoshida
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Wakayama, Japan
| | - Masanobu Tsubaki
- Laboratory of Pharmacotherapy, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido, Sanuki, Kagawa, 769-2193, Japan
| | - Tomoya Takeda
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Ryota Asano
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Ik-Hyun Choi
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Koudai Takimoto
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Ayano Inukai
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Motohiro Imano
- Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka, 589-8511, Japan
| | - Kazufumi Tanabe
- Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Wakayama, Japan
| | - Noriaki Nagai
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan
| | - Shozo Nishida
- Kindai University Faculty of Pharmacy, Kowakae, Higashiosaka, Osaka, 577-8502, Japan.
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Han M, Zhou X, Cheng H, Qiu M, Qiao M, Geng X. Chitosan and hyaluronic acid in colorectal cancer therapy: A review on EMT regulation, metastasis, and overcoming drug resistance. Int J Biol Macromol 2025; 289:138800. [PMID: 39694373 DOI: 10.1016/j.ijbiomac.2024.138800] [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: 11/03/2024] [Revised: 12/04/2024] [Accepted: 12/14/2024] [Indexed: 12/20/2024]
Abstract
Up to 90% of cancer-related fatalities could be attributed to metastasis. Therefore, understanding the mechanisms that facilitate tumor cell metastasis is beneficial for improving patient survival and results. EMT is considered the main process involved in the invasion and spread of CRC. Essential molecular components like Wnt, TGF-β, and PI3K/Akt play a role in controlling EMT in CRC, frequently triggered by various factors such as Snail, Twist, and ZEB1. These factors affect not only the spread of CRC but also determine the reaction to chemotherapy. The influence of non-coding RNAs, especially miRNAs and lncRNAs, on the regulation of EMT is clear in CRC. Exosomes, involved in cell-to-cell communication, can affect the TME and metastasis of CRC. Pharmacological substances and nanoparticles demonstrate promise as efficient modulators of EMT in CRC. Chitosan and HA are two major carbohydrate polymers with considerable potential in inhibiting CRC. Chitosan and HA can be employed to modify nanoparticles to enhance cargo transport for reducing CRC. Additionally, chitosan and HA-modified nanocarriers, which can be utilized as potential approaches in suppressing EMT and reversing drug resistance in CRC, can inhibit EMT and chemoresistance, crucial components in tumorigenesis.
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Affiliation(s)
- Mingming Han
- Department of Pharmacy and Medical Devices, Shandong Academy of Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China
| | - Xi Zhou
- Department of Occupational Pulmonology, Shandong Academy of Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China
| | - Hang Cheng
- Department of Bioanalytical Laboratory (ClinicalLaboratory), Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China
| | - Mengru Qiu
- Department of Occupational Pulmonology, Shandong Academy of Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China.
| | - Meng Qiao
- Department of Bioanalytical Laboratory (ClinicalLaboratory), Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China.
| | - Xiao Geng
- Department of Party Committee Office, Shandong Academy of Occupational Health and Occupational Medicine, Occupational Disease Hospital of Shandong First Medical University, Shandong Province Hospital Occupational Disease Hospital, Jinan, Shandong, China.
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Valenzuela G, Contreras HR, Marcelain K, Burotto M, González-Montero J. Understanding microRNA-Mediated Chemoresistance in Colorectal Cancer Treatment. Int J Mol Sci 2025; 26:1168. [PMID: 39940936 PMCID: PMC11818086 DOI: 10.3390/ijms26031168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial-mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology.
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Affiliation(s)
- Guillermo Valenzuela
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Héctor R. Contreras
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Katherine Marcelain
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
| | - Mauricio Burotto
- Bradford Hill Clinical Research Center, Santiago 8380453, Chile;
| | - Jaime González-Montero
- Basic and Clinical Oncology Department, Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (G.V.); (H.R.C.); (K.M.)
- Center for Cancer Prevention and Control (CECAN), Santiago 8380453, Chile
- Bradford Hill Clinical Research Center, Santiago 8380453, Chile;
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Deli H, Vakili-Ghartavol Z, Asgari Y, Tavoosidana G, Eftekhar E, Ghahremani MH. The expression of exosomal and cellular miRNAs in predicting oxaliplatin resistance in colorectal cancer cells: an in silico and in vitro study. BMC Cancer 2025; 25:46. [PMID: 39789474 PMCID: PMC11715296 DOI: 10.1186/s12885-024-13392-2] [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: 10/10/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a common gastrointestinal cancer, and even though oxaliplatin chemotherapy is effective, there is a high likelihood of relapse, indicating the presence of oxaliplatin-resistant CRC. Therefore, it is crucial to comprehend the molecular mechanisms of oxaliplatin resistance and develop effective strategies to counter drug resistance. Numerous studies have demonstrated the close association between microRNAs (miRNAs) and drug resistance in CRC. In this study, we aimed to identify the essential exosomal and cellular miRNA related to oxaliplatin resistance in the CRC cell line HCT-116. METHODS The miRNA expression profile of CRC cells with resistance to oxaliplatin was analyzed. The effectiveness of diagnostics and biomarker potency of miRNAs were evaluated by receiver operating characteristic (ROC) analysis. Target miRNAs were identified, and the enrichment analysis was assessed based on Gene Ontology (GO), Reactome, and Human Disease Ontology (DO). In vitro experiments, oxaliplatin-resistant HCT-116 cells (HCT116-OXA) were developed, and the exosomes were isolated and characterized from HCT116-OXA and HCT116 cells. The expression of the selected miRNAs was evaluated in HCT116-OXA cells and their exosomes, and they were compared to HCT-116 cells using quantitative real-time PCR. RESULTS This study revealed that a combination of miR-4326, miR-3615, miR-7974, miR-130b-3p, and miR-454-3p exhibited the highest area under the curve (AUC), sensitivity, specificity, and superior diagnostic and predictive performance. In vitro experiments, HCT116-OXA cells displayed reduced early and late apoptosis, a bypass of S phase arrest, prolonged doubling time, and higher IC50 compared to parental cells. The expression of miR-454-3p, miR-130b-3p, miR-7974, miR-3615, and miR-4326 was decreased in HCT116-OXA cells as compared to sensitive cells. However, a significantly higher expression of miR-130b-3p and miR-4326 was observed in the isolated exosomes of HCT116-OXA cells as compared to the sensitive cells. CONCLUSIONS The low expression of miR-454-3p, miR-7974, and miR-3615 in CRC cells or high expression of miR-130b-3p and miR-4326 in isolated exosomes could predict the response to oxaliplatin therapy. This indicates the potential of these specific miRNAs to serve as predictive markers for the response to oxaliplatin therapy.
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Affiliation(s)
- Hoda Deli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeynab Vakili-Ghartavol
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yazdan Asgari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Tavoosidana
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
| | - Mohammad Hossein Ghahremani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Sahebnasagh R, Deli H, Shadboorestan A, Vakili-Ghartavol Z, Salehi N, Komeili-Movahhed T, Azizi Z, Ghahremani MH. Identification of key lncRNAs associated with oxaliplatin resistance in colorectal cancer cells and isolated exosomes: From In-Silico prediction to In-Vitro validation. PLoS One 2024; 19:e0311680. [PMID: 39401197 PMCID: PMC11472961 DOI: 10.1371/journal.pone.0311680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/23/2024] [Indexed: 10/17/2024] Open
Abstract
One of the critical challenges in managing colorectal cancer (CRC) is the development of oxaliplatin (OXP) resistance. Long non-coding RNAs (lncRNAs) have a crucial role in CRC progression and chemotherapy resistance, with exosomal lncRNAs emerging as potential biomarkers. This study aimed to predict key lncRNAs involved in OXP-resistance using in-silico methods and validate them using RT-qPCR methods in CRC cells and their isolated exosomes. Two public datasets, GSE42387 and GSE119481, were downloaded from the GEO database to identify differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) associated with OXP-resistance in the HCT116 cell line. The analysis of GSE42387 revealed 210 DEGs, and GSE119481 identified 73 DEmiRNAs. A protein-protein interaction (PPI) network analysis of the DEGs identified 133 interconnected genes, from which the top ten genes with the highest degree scores were selected. By intersecting predicted miRNAs targeting these genes with the DEmiRNAs, 38 common miRNAs were found. Subsequently, 224 lncRNAs targeting these common miRNAs were predicted. LncRNA-miRNA-mRNA network were constructed and the top five lncRNAs with the highest degree scores were identified. Analysis using the Kaplan-Meier plotter database revealed that the key lncRNAs NEAT1, OIP5-AS1, and MALAT1 are significantly associated with the overall survival of CRC patients. To validate these lncRNAs, OXP-resistant HCT116 sub-cell line (HCT116/OXR) was developed by exposing parental HCT116 cells to gradually increasing concentrations of OXP. Exosomes derived from both HCT116 and HCT116/OXR cells were isolated and characterized utilizing dynamic light scattering (DLS), transmission electron microscopy (TEM), and Western blotting. RT-qPCR confirmed elevated levels of NEAT1, OIP5-AS1, and MALAT1 in HCT116/OXR cells and their exosomes compared to parental HCT116 cells and their exosomes. This study concludes that NEAT1, OIP5-AS1, and MALAT1 are associated with the OXP-resistance in CRC. The high levels of these lncRNAs in exosomes of resistant cells suggest their involvement in intercellular communication and resistance propagation. This positioning makes them promising biomarkers for OXP-resistance in CRC.
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Affiliation(s)
- Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Deli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Shadboorestan
- Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zeynab Vakili-Ghartavol
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Najmeh Salehi
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | | | - Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Feng Z, Zhang S, Han Q, Chu T, Wang H, Yu L, Zhang W, Liu J, Liang W, Xue J, Wu X, Zhang C, Wang Y. Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155647. [PMID: 38703660 DOI: 10.1016/j.phymed.2024.155647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/01/2024] [Accepted: 04/15/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Oxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism. METHODS Two colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin. RESULTS CCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine. CONCLUSIONS Research on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.
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Affiliation(s)
- Zhiqiang Feng
- Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China; Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, PR China
| | - Shuai Zhang
- Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China; Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, PR China
| | - Qiurong Han
- Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China; Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, PR China
| | - Tianhao Chu
- Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China; Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Tianjin, PR China
| | - Huaqing Wang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, PR China
| | - Li Yu
- Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, PR China
| | | | - Jun Liu
- Department of Radiology, The Fourth Central Hospital Affiliated to Nankai University, Tianjin, PR China
| | - Weizheng Liang
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Hebei, PR China
| | - Jun Xue
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Hebei, PR China
| | - Xueliang Wu
- Central Laboratory, The First Affiliated Hospital of Hebei North University, Hebei, PR China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, PR China; Tianjin Institute of Coloproctology, Tianjin, PR China.
| | - Yijia Wang
- Laboratory of Oncologic Molecular Medicine, Tianjin Union Medical Center, Tianjin, PR China.
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Lee C, Park SH, Yoon SK. The E3 ligase HUWE1 increases the sensitivity of CRC to oxaliplatin through TOMM20 degradation. Oncogene 2024; 43:636-649. [PMID: 38184713 DOI: 10.1038/s41388-023-02928-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/17/2023] [Accepted: 12/20/2023] [Indexed: 01/08/2024]
Abstract
Continuous administration of oxaliplatin, the most widely used first-line chemotherapy drug for colorectal cancer (CRC), eventually leads to drug resistance. Increasing the sensitivity of CRC cells to oxaliplatin is a key strategy to overcome this issue. Impairment of mitochondrial function is a pivotal mechanism determining the sensitivity of CRC to oxaliplatin. We discovered an inverse correlation between Translocase of Outer Mitochondrial Membrane 20 (TOMM20) and oxaliplatin sensitivity as well as an inverse relationship between TOMM20 and HECT, UBA, and WWE domain containing E3 ligase 1 (HUWE1) expression in CRC. For the first time, we demonstrated that HUWE1 ubiquitinates TOMM20 directly and also regulates TOMM20 degradation via the PARKIN-mediated pathway. Furthermore, we showed that overexpression of HUWE1 in CRC cells has a negative effect on mitochondrial function, including the generation of ATP and maintenance of mitochondrial membrane potential, leading to increased production of ROS and apoptosis. This effect was amplified when cells were treated simultaneously with oxaliplatin. Our study conclusively shows that TOMM20 is a novel target of HUWE1. Our findings indicate that HUWE1 plays a critical role in regulating oxaliplatin sensitivity by degrading TOMM20 and inducing mitochondrial damage in CRC.
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Affiliation(s)
- Chanhaeng Lee
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea
| | - Sang-Hee Park
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea
| | - Sungjoo Kim Yoon
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea.
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 065-691, Republic of Korea.
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Ma X, Tian F, Li J, Wu Z, Cao L. In Vitro Simulated Ketogenic Diet Inhibits the Proliferation and Migration of Liver Cancer Cells by Reducing Insulin Production and Down-regulating FOXC2 Expression. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2024; 35:726-734. [PMID: 39344752 PMCID: PMC11391236 DOI: 10.5152/tjg.2024.23601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/13/2024] [Indexed: 10/01/2024]
Abstract
Ketogenic diet (KD) may benefit patients with liver cancer, but the underlying mechanism of its anti-cancer effect remains an open issue. This work aimed to explore the influence of simulated KD on the proliferation and migration of cultured hepatoma cells. The low-glucose medium supplemented with β-hydroxybutyrate (BHB-Glow) was utilized to simulate clinical KD treatment. Western blot was utilized for detecting the expression of glycolysis-related proteins, Seahorse XF96 for oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), and ELISA for insulin content. Expression of FOXC2 in liver cancer cells was analyzed by bioinformatics and qPCR. Cell Count Kit-8 (CCK-8) testing kit was utilized for testing cell viability. KD treatment significantly reduced the expression of glycolysis-related proteins in Huh-7 cells, inhibited insulin production in β islet cells, reduced ECAR, and increased OCR. FOXC2 was significantly up-regulated in Huh-7 cell line, and sh-FOXC2 hindered the proliferation and migration of Huh-7 cells. The exogenous addition of insulin promoted the malignant progression of Huh-7 cells. Together, the medium simulating KD environment strengthened the protection of liver cancer cells by reducing insulin production and down-regulating FOXC2 expression. This study confirmed through in vitro cell experiments that KD could inhibit the proliferation and migration of liver cancer cells by targeting down regulation of insulin and FOXC2 expression, providing new theoretical basis for the treatment of liver cancer patients.
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Affiliation(s)
- Xiangming Ma
- Department of Hepatobiliary Surgery, Kailuan General Hospital, Tangshan, Hebei, China
- Laboratory of Hepatobiliary, Kailuan General Hospital, Tangshan, Hebei, China
| | - Fei Tian
- Department of Radiation Oncology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Jian Li
- Department of Diagnostic Radiology, Kailuan General Hospital, Tangshan, Hebei, China
| | - Zhenyu Wu
- Department of Emergency, Kailuan General Hospital, Tangshan, Hebei, China
| | - Liying Cao
- Department of Hepatobiliary Surgery, Kailuan General Hospital, Tangshan, Hebei, China
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Kurter H, Basbinar Y, Ellidokuz H, Calibasi-Kocal G. The Role of Cyanidin-3- O-glucoside in Modulating Oxaliplatin Resistance by Reversing Mesenchymal Phenotype in Colorectal Cancer. Nutrients 2023; 15:4705. [PMID: 38004099 PMCID: PMC10674439 DOI: 10.3390/nu15224705] [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: 09/25/2023] [Revised: 10/11/2023] [Accepted: 10/16/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) plays an important role in the biological and biochemical processes of cells, and it is a critical process in the malignant transformation, and mobility of cancer. Additionally, EMT is one of the main mechanisms contributing to chemoresistance. Resistance to oxaliplatin (OXA) poses a momentous challenge in the chemotherapy of advanced colorectal cancer (CRC) patients, highlighting the need to reverse drug resistance and improve patient survival. In this study, we explored the response of cyanidin-3-O-glucoside (C3G), the most abundant anthocyanin in plants, on the mechanisms of drug resistance in cancer, with the purpose of overcoming acquired OXA resistance in CRC cell lines. METHODS We generated an acquired OXA-resistant cell line, named HCT-116-ROx, by gradually exposing parental HCT-116 cells to increasing concentrations of OXA. To characterize the resistance, we performed cytotoxicity assays and shape factor analyses. The apoptotic rate of both resistant and parental cells was determined using Hoechst 33342/Propidium Iodide (PI) fluorescence staining. Migration capacity was evaluated using a wound-healing assay. The mesenchymal phenotype was assessed through qRT-PCR and immunofluorescence staining, employing E-cadherin, N-cadherin, and Vimentin markers. RESULTS Resistance characterization announced decreased OXA sensitivity in resistant cells compared to parental cells. Moreover, the resistant cells exhibited a spindle cell morphology, indicative of the mesenchymal phenotype. Combined treatment of C3G and OXA resulted in an augmented apoptotic rate in the resistant cells. The migration capacity of resistant cells was higher than parental cells, while treatment with C3G decreased the migration rate of HCT-116-ROx cells. Analysis of EMT markers showed that HCT-116-ROx cells exhibited loss of the epithelial phenotype (E-cadherin) and gain of the mesenchymal phenotype (N-cadherin and Vimentin) compared to HCT-116 cells. However, treatment of resistant cells with C3G reversed the mesenchymal phenotype. CONCLUSION The morphological observations of cells acquiring oxaliplatin resistance indicated the loss of the epithelial phenotype and the acquisition of the mesenchymal phenotype. These findings suggest that EMT may contribute to acquired OXA resistance in CRC. Furthermore, C3G decreased the mobility of resistant cells, and reversed the EMT process, indicating its potential to overcome acquired OXA resistance.
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Affiliation(s)
- Hasan Kurter
- Department of Translational Oncology, Institute of Health Sciences, Dokuz Eylul University, Izmir 35330, Turkey;
| | - Yasemin Basbinar
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir 35330, Turkey;
| | - Hulya Ellidokuz
- Department of Preventive Oncology, Institute of Oncology, Dokuz Eylul University, Izmir 35330, Turkey;
| | - Gizem Calibasi-Kocal
- Department of Translational Oncology, Institute of Oncology, Dokuz Eylul University, Izmir 35330, Turkey;
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10
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Li X, Li X, Liu G, Zhou L, Liu Y, Dou T, Chen X, Wang J. ANP32A Knockdown Attenuates the Malignant Biological Behavior of Colorectal Cancer Cells by Suppressing Epithelial-mesenchymal Transition and ERK Activation. J Cancer 2023; 14:2759-2770. [PMID: 37781083 PMCID: PMC10539559 DOI: 10.7150/jca.84687] [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: 03/26/2023] [Accepted: 08/22/2023] [Indexed: 10/03/2023] Open
Abstract
Acidic leucine rich nuclear phosphoprotein-32A (ANP32A) protein has a variety of functions, such as regulating cell differentiation, influencing cell apoptosis and cell cycle progression. Our previous study demonstrated that high expression of ANP32A was found in the tumor tissues of colorectal cancer (CRC) patients and was positively associated with tumor grading. However, the function and underlying mechanisms of ANP32A in CRC metastasis have not been fully explored. In this study, we found that ANP32A knockdown significantly attenuated the migration and invasion, and epithelial-mesenchymal transition (EMT) in cells. Further mechanistic studies revealed that ANP32A knockdown inhibited the expression of β-catenin and phosphorylated-ERK. The immunofluorescent staining experiment has revealed that ANP32A was expressed in the cell membrane, cytosol and nucleus, and its expression was positively associated with β-catenin expression levels. Moreover, the ability of cell migration and invasion was inhibited, the expression of E-cadherin was enhanced following ANP32A knockdown, and these affects were abolished by an ERK activator PMA, enhanced by an ERK inhibitor PD98059. Moreover, our animal experiment also demonstrated that silenced ANP32A inhibited CRC cell growth, multi-organ metastasis, ERK activation and EMT progression in vivo. Collectively, these findings demonstrated that ANP32A promotes CRC progression and that may be a promising target for the anti-metastasis treatment of CRC.
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Affiliation(s)
- Xiaojuan Li
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Xumei Li
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Guoxiang Liu
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Luwei Zhou
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Yisa Liu
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Tong Dou
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
- School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China
| | - Xu Chen
- Department of Pharmacy, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541199, China
| | - Juan Wang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541001, China
- Faculty of Basic Medicine, Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region 541004, China
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11
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Golbashirzadeh M, Heidari HR, Aghamolayi AA, Fattahi Y, Talebi M, Khosroushahi AY. In vitro siRNA-mediated GPX4 and AKT1 silencing in oxaliplatin resistance cancer cells induces ferroptosis and apoptosis. Med Oncol 2023; 40:279. [PMID: 37632628 DOI: 10.1007/s12032-023-02130-6] [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: 01/20/2022] [Accepted: 02/21/2022] [Indexed: 08/28/2023]
Abstract
Oxaliplatin is a member of platinum-based chemotherapy drugs frequently used in colorectal cancer (CRC). However, resistance to oxaliplatin causes tumor progression and metastasis. Akt1 and Gpx4 are essential regulator genes of apoptosis and ferroptosis pathways. Inhibition of these genes might eradicate oxaliplatin resistance in resistant CRC cells. We compared two cell death strategies to reverse drug resistance in Caco-2 and HT-29 oxaliplatin-resistant cell lines. We used the AKT1-specific siRNA to induce apoptosis. Also, GPX4-specific siRNA and FIN56 were utilized to generate ferroptosis. The effect of these treatments was assessed by reactive oxygen species (ROS) formation, cell viability, and protein expression level assays. Besides, the expression of GPX4, CoQ10, and NRF2 was assessed in both cell lines after treatments. Correctly measuring the expression of these responsible genes and proteins confirms the occurrence of different types of cell death. In addition, the ability of Akt1/ GPX4 siRNA in resensitizing HT-29 and Caco-2 oxaliplatin resistance cells was evaluated. Our finding showed that the upregulation of GPX4/siRNA caused a reduction in GPX4 and CoQ10 expressions in both cell lines. However, the expression level of NRF2 showed the same level in our cell lines, so we observed a downregulation of NRF2 in resistant CRC cell lines. Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.
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Affiliation(s)
- Morteza Golbashirzadeh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Hamid Reza Heidari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran.
| | - Ali Asghar Aghamolayi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Yasin Fattahi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, P.O. 14766-51664, Tabriz, Iran
| | - Mehdi Talebi
- Hematology and Oncology Research Center, Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Yari Khosroushahi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Medical Nanotechnology, Faculty of Advanced Medical Science, Tabriz University of Medical Sciences, Daneshgah Street, P.O.Box 51548-53431, Tabriz, Iran.
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12
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Frerker B, Bock F, Cappel ML, Kriesen S, Klautke G, Hildebrandt G, Manda K. Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells. Int J Mol Sci 2023; 24:10385. [PMID: 37373535 DOI: 10.3390/ijms241210385] [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: 05/15/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, it should be compared whether one combination therapy is more effective than the other. Colorectal cancer cells (HT-29) were treated with irinotecan or oxaliplatin, both alone and in combination with 5-FU, and subsequently irradiated. The cell growth, metabolic activity and proliferation of cells were investigated, and the clonogenic survival was determined. Furthermore, the assessment of radiation-induced DNA damage and the influence of the drugs and their combinations on DNA damage repair was investigated. Treatment with irinotecan or oxaliplatin in combination with 5-FU inhibited proliferation and metabolic activity as well as clonogenic survival and the DNA damage repair capacity of the tumor cells. The comparison of oxaliplatin and irinotecan with simultaneous irradiation showed the same effect of both drugs. When oxaliplatin or irinotecan was combined with 5-FU, tumor cell survival was significantly lower than with monotherapy; however, there was no superiority of either combination regimen. Our results have shown that the combination of 5-FU and irinotecan is as effective as the combination of 5-FU with oxaliplatin. Therefore, our data support the use of FOLFIRI as a radiosensitizer.
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Affiliation(s)
- Bernd Frerker
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Felix Bock
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Marie-Louise Cappel
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Stephan Kriesen
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Gunther Klautke
- Department of Radiation Oncology, Hospital Chemnitz, Bürgerstrasse 2, 09113 Chemnitz, Germany
| | - Guido Hildebrandt
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
| | - Katrin Manda
- Department of Radiotherapy and Radiation Oncology, University Medical Center Rostock, Suedring 75, 18059 Rostock, Germany
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Xu HB, Chen XZ, Wang X, Pan J, Yi-Zhuo Z, Zhou CH. Xihuang pill in the treatment of cancer: TCM theories, pharmacological activities, chemical compounds and clinical applications. JOURNAL OF ETHNOPHARMACOLOGY 2023:116699. [PMID: 37257709 DOI: 10.1016/j.jep.2023.116699] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/17/2023] [Accepted: 05/28/2023] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xihuang pill as a famous traditional Chinese formula has long been used as an adjuvant therapy for cancer. AIM OF THE STUDY This study is aimed at summarizing recent advances in research of Xihuang pill's anti-cancer efficacies from the theoretical basis of traditional Chinese medicine, pharmacological activities, chemical components and its clinical application. MATERIALS AND METHODS The literature information was obtained from several authoritative databases including PubMed, Embase, Cochrane Library, CNKI and Wan Fang before April 30, 2023. We also analyzed the representatively chemical compounds of Xihuang pill in vivo experiments using HPLC-Q/TOF-MS. RESULTS The present study indicated that Xihuang pill, a classic anti-tumor prescription, had efficacies of strengthening body resistance, clearing heat and detoxification, and promoting blood circulation for removing blood stasis. Modern basic researches showed that Xihuang pill played anti-cancer roles through inducing cancer cell apoptosis, inhibiting cell proliferation, migration, invasion and angiogenesis, improving immune function and tumor microenvironment, and regulating related signaling pathways. Its chemical components are primarily consisted of amino acids, terpenoids, fatty acids, fatty acid esters, phenolics, bile acids, bile pigments and volatile oil. Clinically, Xihuang pill, as an adjuvant drug for cancer treatment, was mostly combined with chemotherapy, which could prolong survival, enhance response rate, improve patients' life quality, regulate immune function and alleviate chemotherapy-induced toxicities. CONCLUSIONS This present study suggests that Xihuang pill may be a promising adjuvant therapy for cancer, and proposes the possibility of future research directions for Xihuang pill based on the current research status.
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Affiliation(s)
- Hong-Bin Xu
- Department of Pharmacy, Ningbo First Hospital, Ningbo University, Ningbo, China; Department of Pharmacy, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xian-Zhen Chen
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xia Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing Pan
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhao Yi-Zhuo
- Department of Pharmacy, Ningbo First Hospital, Ningbo University, Ningbo, China
| | - Chen-Hui Zhou
- Department of Neurosurgery, Ningbo First Hospital, Ningbo University, Ningbo, China
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14
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Unraveling the function of epithelial-mesenchymal transition (EMT) in colorectal cancer: Metastasis, therapy response, and revisiting molecular pathways. Biomed Pharmacother 2023; 160:114395. [PMID: 36804124 DOI: 10.1016/j.biopha.2023.114395] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
Colorectal cancer (CRC) is a dangerous form of cancer that affects the gastrointestinal tract. It is a major global health concern, and the aggressive behavior of tumor cells makes it difficult to treat, leading to poor survival rates for patients. One major challenge in treating CRC is the metastasis, or spread, of the cancer, which is a major cause of death. In order to improve the prognosis for patients with CRC, it is necessary to focus on ways to inhibit the cancer's ability to invade and spread. Epithelial-mesenchymal transition (EMT) is a process that is linked to the spread of cancer cells, also known as metastasis. The process transforms epithelial cells into mesenchymal ones, increasing their mobility and ability to invade other tissues. This has been shown to be a key mechanism in the progression of colorectal cancer (CRC), a particularly aggressive form of gastrointestinal cancer. The activation of EMT leads to increases in the spread of CRC cells, and during this process, levels of the protein E-cadherin decrease while levels of N-cadherin and vimentin increase. EMT also contributes to the development of resistance to chemotherapy and radiation therapy in CRC. Non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a role in regulating EMT in CRC, often through their ability to "sponge" microRNAs. Anti-cancer agents have been shown to suppress EMT and reduce the progression and spread of CRC cells. These findings suggest that targeting EMT or related mechanisms may be a promising approach for treating CRC patients in the clinic.
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15
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Lee CC, Lee AW, Wei PL, Liu YS, Chang YJ, Huang CY. In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer. Sci Rep 2023; 13:4366. [PMID: 36927770 PMCID: PMC10020571 DOI: 10.1038/s41598-023-31331-2] [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: 08/11/2022] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein-protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.
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Affiliation(s)
- Cheng-Chin Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Ai-Wei Lee
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC. .,Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.,Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC.,Cancer Research Center and Translational Laboratory, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, ROC.,Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC
| | - Yi-Shin Liu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC. .,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC. .,Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
| | - Chien-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC. .,Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC.
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16
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Samavarchi Tehrani S, Esmaeili F, Shirzad M, Goodarzi G, Yousefi T, Maniati M, Taheri-Anganeh M, Anushiravani A. The critical role of circular RNAs in drug resistance in gastrointestinal cancers. Med Oncol 2023; 40:116. [PMID: 36917431 DOI: 10.1007/s12032-023-01980-4] [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: 01/07/2023] [Accepted: 02/20/2023] [Indexed: 03/16/2023]
Abstract
Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.
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Affiliation(s)
- Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Maniati
- Department of English, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Shi CJ, Xue ZH, Zeng WQ, Deng LQ, Pang FX, Zhang FW, Fu WM, Zhang JF. LncRNA-NEF suppressed oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer through epigenetically inactivating MEK/ERK signaling. Cancer Gene Ther 2023:10.1038/s41417-023-00595-1. [PMID: 36782047 DOI: 10.1038/s41417-023-00595-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 01/06/2023] [Accepted: 02/01/2023] [Indexed: 02/15/2023]
Abstract
A major cause of oxaliplatin chemoresistance in colorectal cancer (CRC) is acquired epithelial-mesenchymal transition (EMT) in cancer cells, making the cancer cells easy to metastasis and recurrence. LncRNA Neighboring Enhancer of FOXA2 (lncRNA-NEF) has been characterized as a tumor suppressor to mediate cancer metastasis in multiple cancer types. However, whether it mediated the drug resistance remains unknown. In the present study, an oxaliplatin-resistant CRC cell line (SW620R) was established and lncRNA-NEF was obviously down-regulated in this resistant cell line. The further loss and gain-of-function studies demonstrated that this lncRNA suppressed oxaliplatin resistance as well as EMT programme in vitro and inhibited metastasis in vivo. Mechanistically, lncRNA-NEF epigenetically promoted the expression of DOK1 (Downstream of Tyrosine kinase 1), a negative regulator of MEK/ERK signaling, by disrupting DNA methyltransferases (DNMTs)-mediated DNA methylation. DOK1, in turn, induced the inactivation of MEK/ERK signaling, forming the lncRNA-NEF/DOK1/MEK/ERK regulatory axis to mediate oxaliplatin resistance in CRC. Collectively, our work reveals the critical function of lncRNA-NEF in mediating the oxaliplatin chemotherapy resistance in CRC, and provides a promising therapeutic strategy for CRC patients with oxaliplatin resistance.
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Affiliation(s)
- Chuan-Jian Shi
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, Guangdong, PR China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China
| | - Zhi-He Xue
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China
| | - Wei-Qiang Zeng
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China
| | - Li-Qiang Deng
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China
| | - Feng-Xiang Pang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Feng-Wei Zhang
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China
| | - Wei-Ming Fu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
| | - Jin-Fang Zhang
- Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, 518000, Guangdong, PR China.
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18
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Hargadon KM, Strong EW. The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer. Technol Cancer Res Treat 2023; 22:15330338231155284. [PMID: 36740986 PMCID: PMC9903043 DOI: 10.1177/15330338231155284] [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] [Indexed: 02/07/2023] Open
Abstract
FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.
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Affiliation(s)
- Kristian M. Hargadon
- Hargadon Laboratory, Hampden-Sydney College, Hampden-Sydney, VA, USA,Kristian M. Hargadon, PhD, Hampden-Sydney College, Brown Student Center, Box 837, Hampden-Sydney, VA 23943, USA.
| | - Elijah W. Strong
- Hargadon Laboratory, Hampden-Sydney College, Hampden-Sydney, VA, USA
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Tavakoli Pirzaman A, Ebrahimzadeh Pirshahid M, Babajani B, Rahmati A, Niknezhad S, Hosseinzadeh R, Taheri M, Ebrahimi-Zadeh F, Doostmohamadian S, Kazemi S. The Role of microRNAs in Regulating Cancer Cell Response to Oxaliplatin-Containing Regimens. Technol Cancer Res Treat 2023; 22:15330338231206003. [PMID: 37849311 PMCID: PMC10586010 DOI: 10.1177/15330338231206003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/18/2023] [Accepted: 10/18/2023] [Indexed: 10/19/2023] Open
Abstract
Oxaliplatin (cyclohexane-1,2-diamine; oxalate; platinum [2+]) is a third-generation chemotherapeutic drug with anticancer effects. Oxaliplatin has a role in the treatment of several cancers. It is one of the few drugs which can eliminate the neoplastic cells of colorectal cancer. Also, it has an influential role in breast cancer, lung cancer, bladder cancer, prostate cancer, and gastric cancer. Although oxaliplatin has many beneficial effects in cancer treatment, resistance to this drug is in the way to cure neoplastic cells and reduce treatment efficacy. microRNAs are a subtype of small noncoding RNAs with ∼22 nucleotides that exist among species. They have diverse roles in physiological processes, including cellular proliferation and cell death. Moreover, miRNAs have essential roles in resistance to cancer treatment and can strengthen sensitivity to chemotherapeutic drugs and regimens. In colorectal cancer, the co-treatment of oxaliplatin with anti-miR-19a can partially reverse the oxaliplatin resistance through the upregulation of phosphatase and tensin homolog (PTEN). Moreover, by preventing the spread of gastric cancer cells and downregulating glypican-3 (GPC3), MiR-4510 may modify immunosuppressive signals in the tumor microenvironment. Treatment with oxaliplatin may develop into a specialized therapeutic drug for patients with miR-4510 inhibition and glypican-3-expressing gastric cancer. Eventually, miR-122 upregulation or Wnt/β-catenin signaling suppression boosted the death of HCC cells and made them more sensitive to oxaliplatin. Herein, we have reviewed the role of microRNAs in regulating cancer cells' response to oxaliplatin, with particular attention to gastrointestinal cancers. We also discussed the role of these noncoding RNAs in the pathophysiology of oxaliplatin-induced neuropathic pain.
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Affiliation(s)
| | | | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Amirhossein Rahmati
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Shokat Niknezhad
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Rezvan Hosseinzadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Taheri
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Faezeh Ebrahimi-Zadeh
- Student Research Committee, school of Medicine, Jahrom University of Medical Science, Jahrom, Iran
| | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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20
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Dey M, Kim MH, Dogan M, Nagamine M, Kozhaya L, Celik N, Unutmaz D, Ozbolat IT. Chemotherapeutics and CAR-T Cell-Based Immunotherapeutics Screening on a 3D Bioprinted Vascularized Breast Tumor Model. ADVANCED FUNCTIONAL MATERIALS 2022; 32:2203966. [PMID: 38938621 PMCID: PMC11209929 DOI: 10.1002/adfm.202203966] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Indexed: 06/29/2024]
Abstract
Despite substantial advancements in development of cancer treatments, lack of standardized and physiologically-relevant in vitro testing platforms limit the early screening of anticancer agents. A major barrier is the complex interplay between the tumor microenvironment and immune response. To tackle this, a dynamic-flow based 3D bioprinted multi-scale vascularized breast tumor model, responding to chemo and immunotherapeutics is developed. Heterotypic tumors are precisely bioprinted at pre-defined distances from a perfused vasculature, exhibit tumor angiogenesis and cancer cell invasion into the perfused vasculature. Bioprinted tumors treated with varying dosages of doxorubicin for 72 h portray a dose-dependent drug response behavior. More importantly, a cell based immune therapy approach is explored by perfusing HER2-targeting chimeric antigen receptor (CAR) modified CD8+ T cells for 24 or 72 h. Extensive CAR-T cell recruitment to the endothelium, substantial T cell activation and infiltration to the tumor site, resulted in up to ≈70% reduction in tumor volumes. The presented platform paves the way for a robust, precisely fabricated, and physiologically-relevant tumor model for future translation of anti-cancer therapies to personalized medicine.
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Affiliation(s)
- Madhuri Dey
- Department of Chemistry, Penn State University, University Park, PA 16802, USA; The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
| | - Myoung Hwan Kim
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Biomedical Engineering Department, Penn State University, University Park, PA 16802, USA
| | - Mikail Dogan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Momoka Nagamine
- Department of Chemistry, Penn State University, University Park, PA 16802, USA; The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA
| | - Lina Kozhaya
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
| | - Nazmiye Celik
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, USA
| | - Derya Unutmaz
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA; University of Connecticut Health Center, Farmington, CT 06032, USA
| | - Ibrahim T Ozbolat
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA; Biomedical Engineering Department, Penn State University, University Park, PA 16802, USA; Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, USA; Materials Research Institute, Penn State University, University Park, PA 16802, USA; Cancer Institute, Penn State University, Hershey, PA 17033, USA; Neurosurgery Department, Penn State University, Hershey, PA 17033, USA; Department of Medical Oncology, Cukurova University, Adana 01330, Turkey
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21
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Luo M, Ji J, Yang K, Li H, Kang L. The role of autophagy in the treatment of colon cancer by chlorin e6 photodynamic therapy combined with oxaliplatin. Photodiagnosis Photodyn Ther 2022; 40:103082. [PMID: 36028170 DOI: 10.1016/j.pdpdt.2022.103082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Photodynamic therapy is a tumour treatment method. Its mechanism mainly induces apoptosis, autophagy, and other ways to cause cell death. Therefore, this study aims to evaluate the therapeutic effect of chlorine e6 photodynamic therapy (Ce6-PDT) combined with oxaliplatin (L-OHP) in colon cancer and to investigate the role of autophagy in L-OHP treatment and Ce6-PDT combined with L-OHP in colon cancer. METHODS CCK-8 assay, Scratch wound healing assay, and Western Blot (WB) were used to identify drug-resistant colon cancer cell line SW620/L-OHP. Annexin V/FITC assay, laser confocal double immunofluorescence staining method and WB were employed to investigate the apoptosis and autophagy changes in Ce6-PDT combined with L-OHP. RESULTS Drug resistance cells SW620/L-OHP were developed under the continuous multi-generation of L-OHP treatment, and the expression of ATP-binding cassette subfamily B member 1 (ABCB1) and ATG5 proteins were increased. The results of immunofluorescence showed that LC3B accumulated in SW620 cells and SW620/L-OHP cells under the treatment of L-OHP. The WB results indicated that LC3B and ATG5 protein expression was increasing in SW620 cells and SW620/L-OHP cells. Inhibition of L-OHP-induced autophagy reduces SW620 cells and SW620/L-OHP cells' viability while increasing apoptosis and the Pro Caspase-3 protein expression. The combination of Ce6-PDT and L-OHP decreased the cell viability, the cell migration ability, the Bcl-2 protein expression, and increased the apoptosis rate, Pro Caspase-3 protein expression in SW620 cells. CONCLUSIONS L-OHP can cause SW620 cells drug resistance. Autophagy plays a protective role in the L-OHP treatment of SW620 cells and SW620/L-OHP cells, and inhibition of autophagy can increase the efficacy of L-OHP. Ce6-PDT combined with L-OHP can further improve the tumor's therapeutic effect, and autophagy inhibition can improve the efficacy of combined therapy.
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Affiliation(s)
- Mengyu Luo
- College of Public Health, Xinjiang Medical University, No 567, SHangde North Road, SHuimogou District, Urumqi, Xinjiang, China; Key Laboratory of Special Environment and Health Research in Xinjiang, China
| | - Jiayin Ji
- College of Public Health, Xinjiang Medical University, No 567, SHangde North Road, SHuimogou District, Urumqi, Xinjiang, China; Key Laboratory of Special Environment and Health Research in Xinjiang, China
| | - Kaizhen Yang
- The First People's Hospital of Urumqi, Urumqi, Xinjiang, China
| | - Hongxia Li
- College of Public Health, Xinjiang Medical University, No 567, SHangde North Road, SHuimogou District, Urumqi, Xinjiang, China; Key Laboratory of Special Environment and Health Research in Xinjiang, China
| | - Ling Kang
- College of Public Health, Xinjiang Medical University, No 567, SHangde North Road, SHuimogou District, Urumqi, Xinjiang, China; Key Laboratory of Special Environment and Health Research in Xinjiang, China.
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22
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Xu X, Duan X, Wang S, Zhang Y, Gao Y, Xu X, Yeerkenbieke G, Zhou J, Li J. Special issue "The advance of solid tumor research in China": Discoidin domain receptor 2 promotes colorectal cancer metastasis by regulating epithelial mesenchymal transition via activating AKT signaling. Int J Cancer 2022; 152:51-65. [PMID: 35904852 DOI: 10.1002/ijc.34227] [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: 01/03/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 11/06/2022]
Abstract
Tumor metastasis is one of the main reasons for the high mortality rate associated with colorectal cancer (CRC). However, its underlying mechanisms have not been fully understood. Here, we reported that the expression of discoidin domain receptor 2 (DDR2) was significantly upregulated in CRC tissues compared with that in normal adjacent tissues. The expression level of DDR2 was negatively associated with prognosis of CRC patients. Therefore, DDR2 may play an oncogenic role in CRC development. Furthermore, DDR2 induced epithelial mesenchymal transition in CRC cells and regulated their invasive and metastatic capacity in vitro and in vivo. Mechanistically, increased DDR2 expression level activated the AKT/GSK-3β/Slug signaling pathway. In conclusion, these findings showed that DDR2 promoted CRC metastasis and DDR2 inhibition might represent an effective therapeutic strategy for local advanced and metastatic CRC treatment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xiaoxiao Xu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Xiaofan Duan
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Shunli Wang
- Tongji University School of Medicine, Shanghai, China.,Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yumei Zhang
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Yuan Gao
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Xiaolin Xu
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Gaoshaer Yeerkenbieke
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Jiuli Zhou
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University School of Medicine, Shanghai, China
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23
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Castaneda M, den Hollander P, Mani SA. Forkhead Box Transcription Factors: Double-Edged Swords in Cancer. Cancer Res 2022; 82:2057-2065. [PMID: 35315926 PMCID: PMC9258984 DOI: 10.1158/0008-5472.can-21-3371] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 02/12/2022] [Accepted: 03/14/2022] [Indexed: 01/07/2023]
Abstract
A plethora of treatment options exist for cancer therapeutics, but many are limited by side effects and either intrinsic or acquired resistance. The need for more effective targeted cancer treatment has led to the focus on forkhead box (FOX) transcription factors as possible drug targets. Forkhead factors such as FOXA1 and FOXM1 are involved in hormone regulation, immune system modulation, and disease progression through their regulation of the epithelial-mesenchymal transition. Forkhead factors can influence cancer development, progression, metastasis, and drug resistance. In this review, we discuss the various roles of forkhead factors in biological processes that support cancer as well as their function as pioneering factors and their potential as targetable transcription factors in the fight against cancer.
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Affiliation(s)
- Maria Castaneda
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Petra den Hollander
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sendurai A. Mani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Corresponding Author: Sendurai A. Mani, Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Suite 910, Houston, TX 77030-3304. Phone: 713-792-9638; E-mail:
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24
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Novoa Díaz MB, Carriere PM, Martín MJ, Calvo N, Gentili C. Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells. World J Gastroenterol 2021; 27:7025-7040. [PMID: 34887626 PMCID: PMC8613645 DOI: 10.3748/wjg.v27.i41.7025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/26/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of mortality from malignant diseases worldwide. In general terms, CRC presents high heterogeneity due to the influence of different genetic and environmental factors; also, the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells, known together as the tumor microenvironment (TME). Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors. Parathyroid hormone-related peptide (PTHrP) is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes. It exerts its effects as a paracrine/autocrine factor, although its mode of action is mainly paracrine. It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia. Eight years ago, when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors, the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited, and no articles had been published regarding to the paracrine action of PTHrP in CRC cells. Based on this and on our previous findings regarding the role of PTH in CRC cells, our purpose in recent years has been to explore the role of PTHrP in CRC. We analyzed the behavior of CRC cells treated with exogenous PTHrP, focalizing in the study of the following events: Survival, cell cycle progression and proliferation, migration, chemoresistance, tumor-associated angiogenesis, epithelial to mesenchymal transition program and other events also associated with invasion, such us the induction of cancer stem cells features. This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes. Recently, we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME, promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells. These investigations establish the basis for our next studies in order to address the clinical applicability of our findings. Recognizing the factors and mechanisms that promote invasion in CRC cells, evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis, to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Matías Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)- INQUISUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Natalia Calvo
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)- INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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25
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Wang C, Yang M, Gu X, Gu Y. Lemur tyrosine kinase-3 (LMTK3) induces chemoresistance to cetuximab in colorectal cancer via the ERK/MAPK pathway. Bioengineered 2021; 12:6594-6605. [PMID: 34516351 PMCID: PMC8806509 DOI: 10.1080/21655979.2021.1974655] [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] [Indexed: 12/24/2022] Open
Abstract
As an oncogenic kinase in multiple cancers, LMTK3 was deeply implicated in cancer pathogenesis. Nevertheless, its biological function in colorectal cancer (CRC) is still unclear. In this study, LMTK3 mRNA expression was assessed by RT-qPCR. LMTK3, phospho-ERK1/2 (p-ERK1/2), ERK1/2, and cleaved caspase-3 protein levels were detected by western blotting. Cetuximab (CTX)-resistant CRC cell models were constructed to investigate the mechanism of LMTK3-regulated CTX resistance in CRC. CTX half-maximal inhibitory concentration (IC50), viability, apoptosis, cell cycle, migration, and invasion of CRC cells were analyzed via Cell Counting Kit-8 (CCK-8), flow cytometry, wound healing, and transwell assays. We found LMTK3 was distinctly upregulated in CRC tissues and cells, particularly in CTX-resistant CRC tissues and cells. LMTK3 inhibition lowered CTX half-maximal inhibitory concentration (IC50) value, inhibited cell viability, induced cell apoptosis, triggered cell-cycle arrest, and impaired cell metastatic capability in CTX-resistant CRC cells. Moreover, we also demonstrated that LMTK3 induced CTX resistance in CRC via the activation of ERK/MAPK signaling in vitro. These results suggested a novel molecular mechanism by which LMTK3 participates in the development of CTX resistance in CRC.
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Affiliation(s)
- Cheng Wang
- Endoscopy and Laparoscopy Center, Changzhou No.3 People's Hospital, Changzhou, Jiangsu, China
| | - Miaomiao Yang
- Endoscopy and Laparoscopy Center, Changzhou No.3 People's Hospital, Changzhou, Jiangsu, China
| | - Xi Gu
- Endoscopy and Laparoscopy Center, Changzhou No.3 People's Hospital, Changzhou, Jiangsu, China
| | - Yanjing Gu
- Endoscopy and Laparoscopy Center, Changzhou No.3 People's Hospital, Changzhou, Jiangsu, China
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26
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Yamamoto-Fukuda T, Akiyama N, Kojima H. Super-enhancer Acquisition Drives FOXC2 Expression in Middle Ear Cholesteatoma. J Assoc Res Otolaryngol 2021; 22:405-424. [PMID: 33861394 PMCID: PMC8329101 DOI: 10.1007/s10162-021-00801-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in middle ear cholesteatoma. It is known that histone acetylation destabilizes the nucleosome and chromatin structure and induces gene activation. The association of histone acetylation with chronic inflammatory diseases has been indicated in recent studies. In this study, we examined the localization of variously modified histone H3 acetylation at lysine 9, 14, 18, 23, and 27 in paraffin-embedded sections of human middle ear cholesteatoma (cholesteatoma) tissues and the temporal bones of an animal model of cholesteatoma immunohistochemically. As a result, we found that there was a significant increase of the expression levels of H3K27ac both in human cholesteatoma tissues and the animal model. In genetics, super-enhancers are clusters of enhancers that drive the transcription of genes involved in cell identity. Super-enhancers were originally defined using the H3K27ac signal, and then we used H3K27ac chromatin immunoprecipitation followed by sequencing to map the active cis-regulatory landscape in human cholesteatoma. Based on the results, we identified increased H3K27ac signals as super-enhancers of the FOXC2 loci, as well as increased protein of FOXC2 in cholesteatoma. Recent studies have indicated that menin-MLL inhibitor could suppress tumor growth through the control of histone H3 modification. In this study, we demonstrated that the expression of FOXC2 was inhibited by menin-MLL inhibitor in vivo. These findings indicate that FOXC2 expression under histone modifications promoted the pathogenesis of cholesteatoma and suggest that it may be a therapeutic target of cholesteatoma.
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Affiliation(s)
- Tomomi Yamamoto-Fukuda
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Naotaro Akiyama
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan
| | - Hiromi Kojima
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan
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27
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Dai XY, Shi L, Li Z, Yang HY, Wei JF, Ding Q. Main N6-Methyladenosine Readers: YTH Family Proteins in Cancers. Front Oncol 2021; 11:635329. [PMID: 33928028 PMCID: PMC8076607 DOI: 10.3389/fonc.2021.635329] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
Among the over 150 RNA modifications, N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNAs, not only in messenger RNAs, but also in microRNAs and long non-coding RNAs. It is a dynamic and reversible process in mammalian cells, which is installed by “writers,” consisting of METTL3, METTL14, WTAP, RBM15/15B, and KIAA1429 and removed by “erasers,” including FTO and ALKBH5. Moreover, m6A modification is recognized by “readers,” which play the key role in executing m6A functions. IYT521-B homology (YTH) family proteins are the first identified m6A reader proteins. They were reported to participate in cancer tumorigenesis and development through regulating the metabolism of targeted RNAs, including RNA splicing, RNA export, translation, and degradation. There are many reviews about function of m6A and its role in various diseases. However, reviews only focusing on m6A readers, especially YTH family proteins are few. In this review, we systematically summarize the recent advances in structure and biological function of YTH family proteins, and their roles in human cancer and potential application in cancer therapy.
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Affiliation(s)
- Xin-Yuan Dai
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Liang Shi
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Zhi Li
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Hai-Yan Yang
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Qiang Ding
- Jiangsu Breast Disease Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
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28
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Micallef I, Baron B. The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer. Noncoding RNA 2021; 7:24. [PMID: 33807355 PMCID: PMC8103280 DOI: 10.3390/ncrna7020024] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.
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Affiliation(s)
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Msida, Malta;
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29
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Ashrafizaveh S, Ashrafizadeh M, Zarrabi A, Husmandi K, Zabolian A, Shahinozzaman M, Aref AR, Hamblin MR, Nabavi N, Crea F, Wang Y, Ahn KS. Long non-coding RNAs in the doxorubicin resistance of cancer cells. Cancer Lett 2021; 508:104-114. [PMID: 33766750 DOI: 10.1016/j.canlet.2021.03.018] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 03/01/2021] [Accepted: 03/17/2021] [Indexed: 12/24/2022]
Abstract
Chemotherapy is the main treatment used for cancer patients failing surgery. Doxorubicin (DOX) is a well-known chemotherapeutic agent capable of suppressing proliferation in cancer cells and triggering apoptosis via inhibiting topoisomerase II activity and producing DNA breaks. This activity of DOX restrains mitosis and cell cycle progression. However, frequent application of DOX results in the emergence of resistance in the cancer cells. It seems that genetic and epigenetic factors can provide DOX resistance of cancer cells. Long non-coding RNAs (lncRNAs) are a subcategory of non-coding RNAs with role in the regulation of several cellular processes such as proliferation, migration, differentiation and apoptosis. LncRNA dysregulation has been associated with chemoresistance, and this profile occurs upon DOX treatment of cancer. In the present review, we focus on the role of lncRNAs in mediating DOX resistance and discuss the molecular pathways and mechanisms. LncRNAs can drive DOX resistance via activating pathways such as NF-κB, PI3K/Akt, Wnt, and FOXC2. Some lncRNAs can activate protective autophagy in response to the stress caused by DOX, which mediates resistance. In contrast, there are other lncRNAs involved in the sensitivity of cancer cells to DOX, such as GAS5, PTCSC3 and FENDRR. Some anti-tumor agents such as polydatin can regulate the expression of lncRNAs, enhancing DOX sensitivity. Overall, lncRNAs are potential players in DOX resistance, and their identification and targeting are of importance in chemosensitivity. Furthermore, these findings can be translated into clinical for treatment of cancer patients.
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Affiliation(s)
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | - Kiavash Husmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Amirhossein Zabolian
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Md Shahinozzaman
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Francesco Crea
- Cancer Research Group-School of Life Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
| | - Yuzhuo Wang
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea.
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Shen X, Zhao K, Xu L, Cheng G, Zhu J, Gan L, Wu Y, Zhuang Z. YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway. Front Genet 2021; 11:592042. [PMID: 33505426 PMCID: PMC7831514 DOI: 10.3389/fgene.2020.592042] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented. Methods To conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification. Results In our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells. Conclusion In summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.
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Affiliation(s)
- Xudong Shen
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Kui Zhao
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Liming Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guilian Cheng
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianhong Zhu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Gan
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yongyou Wu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhixiang Zhuang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Tian Y, Wang J, Qin C, Zhu G, Chen X, Chen Z, Qin Y, Wei M, Li Z, Zhang X, Lv Y, Cai G. Identifying 8-mRNAsi Based Signature for Predicting Survival in Patients With Head and Neck Squamous Cell Carcinoma via Machine Learning. Front Genet 2020; 11:566159. [PMID: 33329703 PMCID: PMC7721480 DOI: 10.3389/fgene.2020.566159] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been characterized by several exclusive features that include differentiation, self-renew, and homeostatic control, which allows tumor maintenance and spread. Recurrence and therapeutic resistance of head and neck squamous cell carcinomas (HNSCC) have been identified to be attributed to CSCs. However, the biomarkers led to the development of HNSCC stem cells remain less defined. In this study, we quantified cancer stemness by mRNA expression-based stemness index (mRNAsi), and found that mRNAsi indices were higher in HNSCC tissues than that in normal tissue. A significantly higher mRNAsi was observed in HPV positive patients than HPV negative patients, as well as in male patients than in female patients. The 8-mRNAsi signature was identified from the genes in two modules which were mostly related to mRNAsi screened by weighted gene co-expression network analysis. In this prognostic signatures, high expression of RGS16, LYVE1, hnRNPC, ANP32A, and AIMP1 focus in promoting cell proliferation and tumor progression. While ZNF66, PIK3R3, and MAP2K7 are associated with a low risk of death. The riskscore of eight signatures have a powerful capacity for 1-, 3-, 5-year of overall survival prediction (5-year AUC 0.77, 95% CI 0.69-0.85). These findings based on stemness indices may provide a novel understanding of target therapy for suppressing HNSCC stem cells.
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Affiliation(s)
- Yuxi Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Juncheng Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Qin
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde, China
| | - Gangcai Zhu
- Department of Otolaryngology Head and Neck Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuan Chen
- Department of Stomatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhixiang Chen
- Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yuexiang Qin
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Ming Wei
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zhexuan Li
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xin Zhang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yunxia Lv
- Department of Thyroid Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Gengming Cai
- Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Quanzhou, Fujian Medical University, Quanzhou, China
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Ashrafizadeh M, Zarrabi A, Hushmandi K, Hashemi F, Hashemi F, Samarghandian S, Najafi M. MicroRNAs in cancer therapy: Their involvement in oxaliplatin sensitivity/resistance of cancer cells with a focus on colorectal cancer. Life Sci 2020; 256:117973. [PMID: 32569779 DOI: 10.1016/j.lfs.2020.117973] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/06/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The resistance of cancer cells into chemotherapy has restricted the efficiency of anti-tumor drugs. Oxaliplatin (OX) being an anti-tumor agent/drug is extensively used in the treatment of various cancer diseases. However, its frequent application has led to chemoresistance. As a consequence, studies have focused in finding underlying molecular pathways involved in OX resistance. MicroRNAs (miRs) are short endogenous non-coding RNAs that are able to regulate vital biological mechanisms such as cell proliferation and cell growth. The abnormal expression of miRs occurs in pathological events, particularly cancer. In the present review, we describe the involvement of miRs in OX resistance and sensitivity. The miRs are able to induce the oncogene factors and mechanisms, resulting in stimulation OX chemoresistance. Also, onco-suppressor miRs can enhance the sensitivity of cancer cells into OX chemotherapy and trigger apoptosis and cell cycle arrest, leading to reduced viability and progression of cancer cells. MiRs can also enhance the efficacy of OX chemotherapy. It is worth mentioning that miRs affect various down-stream targets in OX resistance/sensitivity such as STAT3, TGF-β, ATG4B, FOXO1, LATS2, NF-κB and so on. By identification of these miRs and their upstream and down-stream mediators, further studies can focus on targeting them to sensitize cancer cells into OX chemotherapy and induce apoptotic cell death.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey; Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Turkey
| | | | - Farid Hashemi
- DVM. Graduated, Young Researcher and Elite Club, Kazerun Branch, Islamic Azad University, Kazeroon, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Wang X, Wang C, Xi L, Yu Z. Rap2c as a Novel Biomarker for Predicting Poor Prognosis in Glioma. Onco Targets Ther 2020; 13:3073-3083. [PMID: 32341653 PMCID: PMC7166057 DOI: 10.2147/ott.s247731] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/26/2020] [Indexed: 02/02/2023] Open
Abstract
Objective Rap2c is a member of the Ras superfamily that has been implicated in various types of cancers. However, its role in glioma remains elusive. This study aimed to elucidate the role of Rap2c in glioma and its specific molecular mechanism. Methods We determined the expression of Rap2c in glioma tissues by Western blotting and immunohistochemistry (IHC) assays. The proliferation and apoptosis of cells were explored using CCK-8 and flow cytometry assay, whereas the migration and invasion of glioma cells were determined using transwell assay. The potential mechanism of Rap2c in the migration of glioma cell lines was investigated through Western blotting analysis and transwell assay. BALB/c nude mice were used to establish tumor models to test the effect of Rap2c on cancer metastasis in vivo. Results Our data showed that the protein expression of Rap2c was significantly up-regulated in glioma tissues compared with normal brain tissues, and Rap2c overexpression negatively correlated with 5-year overall survival rate. However, there was no correlation between Rap2c expression and clinicopathological parameters of glioma patients. Overexpression of Rap2c promoted the migration and invasion abilities of glioma cells but had no significant effect on the proliferation of glioma cells. Western blotting analysis revealed that Rap2c overexpression increased the phosphorylation level of extracellular signal-related kinase1/2 (ERK1/2), and this effect was abolished with U0126, a selective MEK inhibitor. Furthermore, overexpression of Rap2c induced lung metastasis of glioma cells in xenograft models. Conclusion These findings indicate that high Rap2c expression predicts poor prognosis in glioma. Rap2c-mediated ERK1/2 phosphorylation initiates EMT cascade and promotes migration and invasion of glioma cells. Thus, targeting Rap2c and ERK signaling pathway could be a novel treatment modality for glioma.
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Affiliation(s)
- Xiucun Wang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People's Republic of China.,Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, People's Republic of China
| | - Cheng Wang
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, People's Republic of China
| | - Lin Xi
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, People's Republic of China
| | - Zhengquan Yu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, People's Republic of China
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