MiR-125b-5p Is Involved in Sorafenib Resistance through Ataxin-1-Mediated Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

Hirao, Akihiro; Sato, Yasushi; Tanaka, Hironori; Nishida, Kensei; Tomonari, Tetsu; Hirata, Misato; Bando, Masahiro; Kida, Yoshifumi; Tanaka, Takahiro; Kawaguchi, Tomoyuki; Wada, Hironori; Taniguchi, Tatsuya; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Tanahashi, Takao; Takayama, Tetsuji

doi:10.3390/cancers13194917

Cited by 22 publications

(17 citation statements)

References 52 publications

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“…Mechanistically, miR-125b-5p promoted the EMT process and conferred stemness characteristics in PLC/PRF5-R1/R2 cells by targeting ATXN1, leading to the reduction of sorafenib sensitivity in HCC. Consistent with this, ATXN1 knockdown in HCC cells exhibited a higher CSC population and an EMT phenotype ( 174 ). Chaudhary et al.…”

Section: Mechanisms Of Ncrnas In Mediating Cancer Drug Resistancesupporting

confidence: 66%

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Zhou

Jia

et al. 2022

Front. Oncol.

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Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients’ health and life. Systemic chemotherapy remains the first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with the potential to effectively extend patient survival. However, the development of drug resistance seriously limits the clinical efficiency of chemotherapy and ultimately results in treatment failure and patient death. A large number of studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, are widely involved in the regulation of cancer drug resistance. Their dysregulation contributes to the development of cancer drug resistance by modulating the expression of specific target genes involved in cellular apoptosis, autophagy, drug efflux, epithelial-to-mesenchymal transition (EMT), and cancer stem cells (CSCs). Moreover, some ncRNAs also possess great potential as efficient, specific biomarkers in diagnosis and prognosis as well as therapeutic targets in cancer patients. In this review, we summarize the recent findings on the emerging role and underlying mechanisms of ncRNAs involved in cancer drug resistance and focus on their clinical applications as biomarkers and therapeutic targets in cancer treatment. This information will be of great benefit to early diagnosis and prognostic assessments of cancer as well as the development of ncRNA-based therapeutic strategies for cancer patients.

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Section: Mechanisms Of Ncrnas In Mediating Cancer Drug Resistancesupporting

confidence: 66%

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Zhou

Jia

et al. 2022

Front. Oncol.

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“…Studies have shown that ER stress plays a crucial role in activation of hepatic stellate cells [ 114 , 115 ] and that blocking the IRE1α–XBP1 pathway can significantly reduce liver fibrosis and tumor burden in several animal models for cirrhosis [ 47 ] and HCC [ 22 ]. Jia et al sought to provide a deeper investigation regarding the involvement of CAFs in epithelial–mesenchymal transition (EMT) in HCC [ 116 ], a process that is known to contribute to drug resistance in HCC and many other solid tumors [ 117 , 118 ]. Proteomic analyses identified that transglutaminase 2 (TG2) is substantially overexpressed in HCC cells that have obtained an EMT phenotype.…”

Section: Role Of the Tumor Microenvironmentmentioning

confidence: 99%

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Khaled

Kopsida

Lennernäs

et al. 2022

Cells

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Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

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“…In HCC, stemness properties are closely associated with drug resistance, tumor metastasis, and recurrence [39]. Stemness properties are closely associated with the EMT phenotype, which was previously reported to contribute to sorafenib resistance in HCC [40,41]. Several other studies also reported that stemness properties are closely associated with sorafenib resistance in HCC [42].…”

Section: Discussionmentioning

confidence: 92%

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

et al. 2022

Pharmaceutics

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Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial–mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC.

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MiR-125b-5p Is Involved in Sorafenib Resistance through Ataxin-1-Mediated Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma

Cited by 22 publications

References 52 publications

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

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