MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

Liang, Yuehui; Liang, Qi; Qiao, Liang; Xiao, Fang

doi:10.3389/fonc.2020.00920

Cited by 31 publications

(23 citation statements)

References 125 publications

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“…HCC is the most prevalent primary liver cancer, accounting for 70-85% of all cases with primary liver cancer, while metastasis is the main death cause of HCC [13]. miRNAs are critically involved in gene expression regulation at both transcriptional and posttranscriptional levels during the initiation and progression of various types of cancer, including HCC [14]. Increasing studies have shown that miRNAs can influence HCC occurrence by regulating oncogenes and tumor suppressor genes [15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA-Binding Protein 6

Huo

Zhou

2021

BioMed Research International

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MicroRNAs (miRs) are regulators of the formation and development of hepatocellular carcinoma (HCC). The biological role of miR-4325 in HCC has yet to be determined. This study is aimed at dissecting the role of miR-4325 in HCC and the underlying mechanism. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect miR-4325 expression in HCC tissue specimens and cells. Cell proliferation, migration, and invasion were assessed by using the MTT assay and Transwell assay, respectively. The miR-4325 target was predicted based on bioinformatics analysis and validated using the dual-luciferase reporter assay. Rescue experiments in the cells were utilized to functionally characterize the downstream molecular targets of miR-4325. We observed that miR-4325 expression levels were significantly reduced in both HCC tissue specimens and cell lines. Meanwhile, a lower miR-4325 level was associated with a poorer prognosis. Gain and loss of function assays revealed that miR-4325 markedly downregulated HCC cell growth, migration, and invasion. Moreover, we identified GATA-binding protein 6 (GATA6) as a miR-4325 target and found that GATA6 was abnormally expressed in HCC. Rescue assays demonstrated that the regulatory function of miR-4325 in HCC was mediated by GATA6. Taken together, miR-4325 suppresses HCC cell growth, migration, and invasion by targeting GATA6, suggesting that miR-4325 may potentially serve as a novel therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA-Binding Protein 6

Huo

Zhou

2021

BioMed Research International

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“…MicroRNAs (miRNAs/miRs) can directly suppress the target gene translation by binding to the 3′ untranslated region (3′ UTR) of the target mRNA (Bazavar et al., 2020; Liang et al., 2020; Singh et al., 2012). Dysregulation of miRNAs promotes malignant phenotypes, such as tumour growth, metastasis and appearance of MDR through regulating downstream targets and associated pathways (Mutlu et al., 2016).…”

Section: Introductionmentioning

confidence: 99%

miR‐21 inhibition reverses doxorubicin‐resistance and inhibits PC3 human prostate cancer cells proliferation

Zhao

Ning²,

Wang

et al. 2021

Andrologia

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Many approaches have been examined to reversing multidrug resistance (MDR), but sub‐optimal target‐based strategies have limited their efficacy. Herein, we investigate microRNA (miR‐21) suppression on the doxorubicin (DOX)‐sensitisation of the DOX‐resistant (PC3/DOX) cell line in prostate cancer (PCa). Expression levels of miR‐21, P‐glycoprotein (P‐gp), MDR‐1 and PTEN evaluated in PC3/DOX cancer cells by qRT‐PCR and western blot analyses. The cytotoxic effects of transfected of miR‐21 were assessed by MTT assay for 72 hr. Rhodamine123 (Rh123) assay was employed to define the activity of P‐gp. Apoptosis was detected by Flow cytometry. As expected, miR‐21 was expressed highly in PC3/DOX cells (p < 0.05). It was shown that miRNA‑21 suppression considerably hindered PC3/DOX cell viability. miR‑21 suppression dramatically downregulated P‐gp expression and activity in DOX‐resistance cells and abolished MDR by an increment of intracellular accumulation of DOX in PC3/DOX cells (p < 0.05). PTEN is a key modulator of the PI3K/Akt/P‐gp cascade, which miR‐21 suppression led to the upregulation of PTEN and sequentially lower‐expression of P‐gp that reversed MDR. Also, miR‐21 repression enhanced the apoptosis rate of PC3/DOX cells. The findings of this paper contribute to the current understanding of the functions of miR‐21 in MDR‐reversing in PCa.

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“…It has been demonstrated by our group and others that microRNAs (miRs) represent powerful small RNA molecules that modulate drug resistance related features in HCC [ 10 , 24 ]. In recent years, miR-622 has emerged as one of the most promising tumorsuppressive microRNAs, which is underscored by multiple studies addressing its potent role in diverse types of cancer [ 6 , 10 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma

Fritz

Malek

Gaza

et al. 2021

Cancers

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Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.

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MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

Cited by 31 publications

References 125 publications

MicroRNA-4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA-Binding Protein 6

MicroRNA-4325 Suppresses Cell Progression in Hepatocellular Carcinoma via GATA-Binding Protein 6

miR‐21 inhibition reverses doxorubicin‐resistance and inhibits PC3 human prostate cancer cells proliferation

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma

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