Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer

Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.

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Overcoming Therapeutic Resistance of Bone Sarcomas: Overview of the Molecular Mechanisms and Therapeutic Targets for Bone Sarcoma Stem Cells

Stem Cells International ◽

10.1155/2016/2603092 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Tomohiro Fujiwara ◽

Toshifumi Ozaki

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Therapeutic Targets ◽

Treatment Strategies ◽

Bone Sarcoma ◽

Molecular Heterogeneity ◽

Bone Sarcomas ◽

Patient Prognosis

Bone sarcomas are heterogeneous malignant tumors that exhibit clinical, histological, and molecular heterogeneity. Recent progress in their multimodal treatment has gradually improved patient prognosis; however, drug resistance and distant metastasis remain unresolved clinical problems. Recent investigations have suggested the existence of cancer stem-like cells (CSCs) in bone sarcomas, which represent a subpopulation of tumor cells with high tumor-forming ability. The hallmarks of CSCs include tumor- and metastasis-forming potential and drug resistance, which are responsible for poor prognoses of bone sarcoma patients. Therefore, elucidation of the molecular mechanisms of CSCs and identification of therapeutic targets could contribute to novel treatment strategies for bone sarcomas and improve patient prognosis. This paper provides an overview of the accumulating knowledge on bone sarcoma stem cells and preclinical analyses to overcome their lethal phenotypes, in addition to a discussion of their potential for novel therapeutics for bone sarcomas.

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Cancer cachexia: molecular mechanism and pharmacological management

Biochemical Journal ◽

10.1042/bcj20201009 ◽

2021 ◽

Vol 478 (9) ◽

pp. 1663-1688

Author(s):

Yonghua Li ◽

Huan Jin ◽

Yibing Chen ◽

Ting Huang ◽

Yanjun Mi ◽

...

Keyword(s):

Adipose Tissue ◽

Cancer Cachexia ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Life Quality ◽

Signal Pathways ◽

Pharmacological Management ◽

Early Phase Trials ◽

Molecular Substrates ◽

Underlying Mechanisms

Cancer cachexia often occurs in malignant tumors and is a multifactorial and complex symptom characterized by wasting of skeletal muscle and adipose tissue, resulting in weight loss, poor life quality and shorter survival. The pathogenic mechanism of cancer cachexia is complex, involving a variety of molecular substrates and signal pathways. Advancements in understanding the molecular mechanisms of cancer cachexia have provided a platform for the development of new targeted therapies. Although recent outcomes of early-phase trials have showed that several drugs presented an ideal curative effect, monotherapy cannot be entirely satisfactory in the treatment of cachexia-associated symptoms due to its complex and multifactorial pathogenesis. Therefore, the lack of definitive therapeutic strategies for cancer cachexia emphasizes the need to develop a better understanding of the underlying mechanisms. Increasing evidences show that the progression of cachexia is associated with metabolic alternations, which mainly include excessive energy expenditure, increased proteolysis and mitochondrial dysfunction. In this review, we provided an overview of the key mechanisms of cancer cachexia, with a major focus on muscle atrophy, adipose tissue wasting, anorexia and fatigue and updated the latest progress of pharmacological management of cancer cachexia, thereby further advancing the interventions that can counteract cancer cachexia.

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Long noncoding RNA FAM225A promotes the malignant progression of gastric cancer through the miR-326/PADI2 axis

Cell Death Discovery ◽

10.1038/s41420-021-00809-1 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Xiang Ma ◽

Gang Wang ◽

Hao Fan ◽

Zengliang Li ◽

Wangwang Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Therapeutic Targets ◽

In Vitro Assays ◽

Advanced Tumor Stage ◽

Advanced Tumor ◽

Mechanistic Investigation

AbstractGastric cancer (GC) is a global health problem and further studies of its molecular mechanisms are needed to identify effective therapeutic targets. Although some long noncoding RNAs (lncRNAs) have been found to be involved in the progression of GC, the molecular mechanisms of many GC-related lncRNAs remain unclear. In this study, a series of in vivo and in vitro assays were performed to study the relationship between FAM225A and GC, which showed that FAM225A levels were correlated with poor prognosis in GC. Higher FAM225A expression tended to be correlated with a more profound lymphatic metastasis rate, larger tumor size, and more advanced tumor stage. FAM225A also promoted gastric cell proliferation, invasion, and migration. Further mechanistic investigation showed that FAM225A acted as a miR-326 sponge to upregulate its direct target PADI2 in GC. Overall, our findings indicated that FAM225A promoted GC development and progression via a competitive endogenous RNA network of FAM225A/miR-326/PADI2 in GC, providing insight into possible therapeutic targets and prognosis of GC.

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Chemotherapy-elicited exosomal miR-378a-3p and miR-378d to promote breast cancer stemness and chemoresistance via the activation of EZH2/STAT3 signaling.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12615 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12615-e12615

Author(s):

Jin Zhang

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Neoadjuvant Chemotherapy ◽

Pathologic Complete Response ◽

Chemotherapeutic Agents ◽

Cell Counting ◽

Chemotherapy Response ◽

Mouse Tumor ◽

Response To Chemotherapy ◽

Serum Exosomes

e12615 Background: Not all breast cancer (BC) patients who receive neoadjuvant chemotherapy achieve a pathologic complete response (pCR), but the reasons for this are unknown. Previous studies have shown that exosomes produced in the tumor microenvironment in response to chemotherapy promote a chemotherapy-resistant phenotype in tumors. However, the role of BC chemo-elicited exosomes in regulating chemoresistance is poorly understood. Methods: Using commercial kits, serum exosomes were extracted from patients before neoadjuvant chemotherapy, after one cycle of chemotherapy and after four cycles of chemotherapy consisting of doxorubicin (DOX) and paclitaxel (PTX). Their miRNAs were sequenced, and the correlation between the sequencing results and chemotherapy effects was further verified by RT-qPCR using patient serum exosomes. Cell Counting Kit-8 (CCK-8) was used to detect chemosensitivity. Stemness was assessed by CD44+/CD24- population analysis and mammosphere formation assays. Chromatin immunoprecipitation (ChIP) experiments were performed to verify the binding of signal transducer and activator of transcription 3 (STAT3) to the promoter of miRNAs. Results: Here, we provide clinical evidence that chemotherapy-elicited exosomal miR-378a-3p and miR-378d are closely related to the chemotherapy response and that exosomes produced by BC cells after stimulation with DOX or PTX deliver miR-378a-3p and miR-378d to neighboring cells to activate WNT and NOTCH stemness pathways and induce drug resistance by targeting Dickkopf 3 (DKK3) and NUMB. In addition, STAT3, which is enhanced by zeste homolog 2 (EZH2), bound to the promoter regions of miR-378a-3p and miR-378d, thereby increasing their expression in exosomes. More importantly, chemotherapeutic agents combined with the EZH2 inhibitor tazemetostat reversed chemotherapy-elicited exosome induced drug resistance in a nude mouse tumor xenograft model. Conclusions: This study revealed a novel mechanism of acquired chemoresistance whereby chemotherapy activates the EZH2/STAT3 axis in BC cells, which then secrete chemotherapy-elicited exosomes enriched in miR-378a-3p and miR-378d. These exosomes are absorbed by chemotherapy-surviving BC cells, leading to activation of WNT and NOTCH stem cell pathways via the targeting of DKK3 and NUMB and subsequently resulting in drug resistance. Therefore, blocking this adaptive mechanism during chemotherapy may reduce the development of chemotherapy resistance and maximize the therapeutic effect.

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Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ATG5 Pathway in Gastric Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000488742 ◽

2018 ◽

Vol 46 (2) ◽

pp. 847-859 ◽

Cited By ~ 20

Author(s):

Guoqing Pei ◽

Meng Luo ◽

Xiaochun Ni ◽

Jugang Wu ◽

Shoulian Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Chemotherapy Resistance ◽

Cell Counting ◽

Cancer Resistance ◽

Glycoprotein P ◽

Real Time Quantitative Pcr ◽

Mucosal Tissues ◽

Underlying Mechanisms

Background/Aims: Metadherin (MTDH) is overexpressed in some malignancies and enhances drug resistance; however, its role in gastric cancer (GC) and the underlying mechanisms remain largely unexplored. Here, we explore the mechanism by which MTDH induces drug resistance in GC. Methods: We analysed the level of MTDH in GC and adjacent normal gastric mucosal tissues by real-time quantitative PCR (q-PCR). We also analysed the level of autophagy by western blot analysis, confocal microscopy, and transmission electron microscopy after MTDH knockdown and overexpression, and examined fluorouracil (5-FU) resistance by Cell Counting Kit-8 at the same time. Finally, GC patient-derived xenograft tumours were used to demonstrate 5-FU resistance. An AMPK pathway inhibitor was applied to determine the molecular mechanisms of autophagy. Results: MTDH expression was significantly increased in the GC specimens compared with that in the adjacent normal gastric mucosal tissues. Further study showed a positive correlation between the expression level of MTDH and 5-FU resistance. MTDH overexpression in MKN45 cells increased the levels of P-glycoprotein (P-gp) and promoted 5-FU resistance, while inhibition of MTDH showed the opposite result. The simultaneous inhibition of autophagy and overexpression of MTDH decreased the levels of P-gp and inhibited 5-FU resistance. Moreover, MTDH induced AMPK phosphorylation, regulated ATG5 expression, and finally influenced autophagy, suggesting that MTDH may activate autophagy via the AMPK/ATG5 signalling pathway. Our findings reveal a unique mechanism by which MTDH promotes GC chemoresistance and show that MTDH is a potential target for improved chemotherapeutic sensitivity and GC patient survival. Conclusions: MTDH-stimulated cancer resistance to 5-FU may be mediated through autophagy activated by the AMPK/ATG5 pathway in GC.

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Exosomal Micro RNA-107 Reverses Chemotherapeutic Drug Resistance of Gastric Cancer Cells Through HMGA2/mTOR/P-gp Pathway

10.21203/rs.3.rs-540926/v1 ◽

2021 ◽

Author(s):

Lu Jiang ◽

Yan Zhang ◽

Linghui Guo ◽

Chaoyang Liu ◽

Weihong Ren

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Chemotherapeutic Agents ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Reporter Assay ◽

Gastric Cancer Cells ◽

Chemotherapy Drug ◽

Chemotherapy Drugs

Abstract Background: RNA cargo in exosomes，especially microRNAs (miRNAs), play an important role in the chemotherapy drug resistance of human cancers. However, the role and mechanism of exosomal miR-107 on multidrug resistance of gastric cancer cells was still not clear. In this study, we sought to explore whether exosomal miR-107 could reverse theresistance of gastric cancer cells to the chemotherapy drugs. Methods: We extracted exosomes from sensitive (SGC-7901, MGC-803) and resistant (SGC-7901/5-FU) gastric cancer cells by ultracentrifugation and the isolated exosomes were identified using transmission electron microscopy (TEM) and dynamic light scattering analysis (DLS). The expression of miR-107 and high mobility group A2 (HMGA2) were detected by real-time quantitative PCR (RT-qPCR). MTT assay was used to investigate the effect of exosomes on gastric cancer cells growth in vitro. The uptake of exosomes by recipient cells were observed using a fluorescence microscope. The predicted target relationship between miR-107 and HMGA2 was verified by gauss-luciferase reporter assay. The expression of HMGA2, p-mTOR/mTOR, P-gp and other exosomal indicated marker proteins were detected by western blot. Results: Our results indicated that the isolated exosomes were demostrated typically cup-like lipid bilayer membrans structure. SGC-7901/5-FU cells were cross-resistant to chemotherapy drug cisplatin (DDP), and the sensitive cells-secreted exosomes drastically reversed the resistance of the resistant gastric cells to the chemotherapeutic drugs,which was verificated by exosomal inhibitor GW4896. Mechanistically, the reversal effect were mainly mediated by exosome-secreted miR-107 through downregulating the expression of targert molecular HMGA2, and inhibiting HMGA2/mTOR/P-gp pathway, which were proofed by luciferase reporter assay and rescue assay. Conclusions: These findings demonstrated that exosome-transmitted miR-107 significantly enhanced the sensitivity of resistant gastric cancer cells to chemotherapeutic agents by mediating the HMGA2/mTOR/P-gp axis and appling exosomal miR-107 may be a novel target in gastric cancers treatment.

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LncRNA FEZF1-AS1 Promotes Multi-Drug Resistance of Gastric Cancer Cells via Upregulating ATG5

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.749129 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zhifu Gui ◽

Zhenguo Zhao ◽

Qi Sun ◽

Guoyi Shao ◽

Jianming Huang ◽

...

Keyword(s):

Gastric Cancer ◽

Drug Resistance ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Underlying Mechanism ◽

Multi Drug Resistance ◽

Gastric Cancer Cells ◽

Poor Overall Survival

Long non-coding RNAs (lncRNAs) play important roles in human cancers including gastric cancer (GC). Dysregulation of lncRNAs is involved in a variety of pathological activities associated with gastric cancer progression and chemo-resistance. However, the role and molecular mechanisms of FEZF1-AS1 in chemoresistance of GC remain unknown. In this study, we aimed to determine the role of FEZF1-AS1 in chemoresistance of GC. The level of FEZF1-AS1 in GC tissues and GC cell lines was assessed by qRT-PCR. Our results showed that the expression of FEZF1-AS1 was higher in gastric cancer tissues than in adjacent normal tissues. Multivariate analysis identified that high level of FEZF1-AS1 is an independent predictor for poor overall survival. Increased FEZF1-AS1 expression promoted gastric cancer cell proliferation in vitro. Additionally, FEZF1-AS1 was upregulated in chemo-resistant GC tissues. The regulatory effect of FEZF1-AS1 on multi-drug resistance (MDR) in GC cells and the underlying mechanism was investigated. It was found that increased FEZF1-AS1 expression promoted chemo-resistance of GC cells. Molecular interactions were determined by RNA immunoprecipitation (RIP) and the results showed that FEZF1-AS1 regulated chemo-resistance of GC cells through modulating autophagy by directly targeting ATG5. The proliferation and autophagy of GC cells promoted by overexpression of LncFEZF1-AS1 was suppressed when ATG5 was knocked down. Moreover, knockdown of FEZF1-AS1 inhibited tumor growth and increased 5-FU sensitivity in GC cells in vivo. Taken together, this study revealed that the FEZF1-AS1/ATG5 axis regulates MDR of GC cells via modulating autophagy.

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Mechanisms and Advances in Anti-Ovarian Cancer with Natural Plants Component

Molecules ◽

10.3390/molecules26195949 ◽

2021 ◽

Vol 26 (19) ◽

pp. 5949

Author(s):

Jingyuan Wu ◽

Tuoyu Zhou ◽

Yinxue Wang ◽

Yanbiao Jiang ◽

Yiqing Wang

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Malignant Tumors ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Therapeutic Effects ◽

Dna Lesion ◽

Female Reproductive Health ◽

Wide Availability

Ovarian cancer ranks seventh in the most common malignant tumors among female disease, which seriously threatens female reproductive health. It is characterized by hidden pathogenesis, missed diagnosis, high reoccurrence rate, and poor prognosis. In clinic, the first-line treatment prioritized debulking surgery with paclitaxel-based chemotherapy. The harsh truth is that female patients are prone to relapse due to the dissemination of tumor cells and drug resistance. In these circumstances, the development of new therapy strategies combined with traditional approaches is conductive to improving the quality of treatment. Among numerous drug resources, botanical compounds have unique advantages due to their potentials in multitarget functions, long application history, and wide availability. Previous studies have revealed the therapeutic effects of bioactive plant components in ovarian cancer. These natural ingredients act as part of the initial treatment or an auxiliary option for maintenance therapy, further reducing the tumor and metastatic burden. In this review, we summarized the functions and mechanisms of natural botanical components applied in human ovarian cancer. We focused on the molecular mechanisms of cell apoptosis, autophagy, RNA and DNA lesion, ROS damage, and the multiple-drug resistance. We aim to provide a theoretical reference for in-depth drug research so as to manage ovarian cancer better in clinic.

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Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽

10.3390/cancers13205117 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5117

Author(s):

Chandra K. Maharjan ◽

Po Hien Ear ◽

Catherine G. Tran ◽

James R. Howe ◽

Chandrikha Chandrasekharan ◽

...

Keyword(s):

Drug Resistance ◽

Neuroendocrine Tumors ◽

Molecular Mechanisms ◽

Treatment Options ◽

Somatostatin Receptor ◽

Therapeutic Targets ◽

Model Systems ◽

Pancreatic Neuroendocrine Tumors ◽

Acquired Drug Resistance ◽

Molecular Alterations

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

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Signaling Pathways in Cervical Cancer Chemoresistance: Are microRNAs and Long-Noncoding RNAs the Main Culprits?

10.20944/preprints202004.0294.v1 ◽

2020 ◽

Author(s):

Seyyed Reza Mousavi ◽

Nima Hemmat ◽

Hossein Bannazadeh Baghi ◽

Afshin Derakhshani ◽

Stefania Tommasi ◽

...

Keyword(s):

Cervical Cancer ◽

Drug Resistance ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Bioinformatic Analysis ◽

Aberrant Expression ◽

Recurrent Cervical Cancer ◽

Response To Chemotherapy ◽

Wide Range ◽

Non Coding Rnas

Cervical cancer is known as one of the most important cancers in women worldwide. Chemotherapy is a standard treatment for advanced/recurrent cervical cancer in which the prognosis of the disease is really poor and the 1-year survival chance in these patients is maximally 20%. However, resistance to anticancer drugs is a major problem in treating cancer. Cervical cancer stem cells are considered as a fundamental cause of chemo and radio-resistance and also relapse after primary successful treatment. Signaling pathways include a wide range of molecular mechanisms contribute to drug resistance. Recently, microRNAs (miRNAs) are announced as a group of molecular biomarkers involving in response to chemotherapy in cancer patients. As the miRNAs, there are some long non-coding RNAs (LncRNAs) which their aberrant expression is considered as a biomarker for monitoring chemoresistance. In this review, we summarized current reports about the involvement of signaling pathways during chemoresistance in cervical cancer. Then, genes that have been demonstrated their involvement during drug resistance in cervical cancer were tabulated. Further, miRNAs that have been reported as biomarkers during treatment are listed. By bioinformatic analysis, we predictedmiR-335-5p and miR-16-5p as the most potential biomarkers for monitoring resistance to chemotherapy. Finally, long non-coding RNAs that have been introduced in recent studies as novel biomarkers during the response to chemotherapy were mentioned.

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