Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells

Chen, Hsin An; Li, Chi Cheng; Lin, Yi-Chun; Wang, Tso Fu; Chen, Ming Cheng; Su, Yen‐Hao; Yeh, Yu Lan; Padma, Viswanadha Vijaya; Liao, Po Hsiang; Huang, Chih‐Yang

doi:10.18632/aging.202908

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…The deregulation of miR-107 expression has been implicated in various human cancers, with its role as either a tumor suppressor or an oncogene being debated [41][42][43]. This debate also extends to liver cancer, where studies have reported both carcinogenic [44] and tumor-suppressive effects of miR-107 [45,46].…”

Section: Discussionmentioning

confidence: 99%

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Castoldi,

Roy,

Lohr

et al. 2023

Preprint

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Background & AimsIn hepatocellular carcinoma, there is a lack of successful translation of experimental targets identified in mouse models to human patients. In this study, we used a comprehensive transcriptomic approach in mice to identify novel potential targets for therapeutic intervention in humans.MethodsWe analysed combined genome-wide miRNA and mRNA expression data in three pathogenically distinct mouse models of liver cancer. Effects of target genes on hepatoma cell fitness were evaluated by proliferation, survival and motility assays. TCGA and GEO databases, in combination with tissue microarrays (TMA), were used to validate the mouse targets and their impact on human HCC prognosis. Finally, the functional effects of the identified targets on tumorigenesis and tumor therapy were tested in hydrodynamic tail vein injection (HDTVi)-based preclinical HCC modelsin vivo.ResultsThe expression of miR-107 was found to be significantly reduced in mouse models of liver tumors of various etiologies and in cohorts of human HCC patients. Overexpression of miR-107 or inhibition of its novel target Kinesin family member 23 (Kif23) significantly reduced proliferation by interfering with cytokinesis, thereby controlling survival and motility of mouse and human hepatoma cells. In humans, KIF23 expression was found to be a prognostic marker in liver cancer, with high expression associated with poor prognosis. HDTVi of vectors carrying either pre-miR- 107 or anti-Kif23 shRNA inhibited the development of highly aggressive cMyc-NRas- induced liver cancers in mice.ConclusionsDisruption of the miR-107/Kif23 axis inhibited hepatoma cell proliferationin vitroand prevented oncogene-induced liver cancer developmentin vivo, offering a novel potential avenue for the treatment of HCC in humans.Impact and implicationsA comprehensive analysis integratingin silicoprediction, miRNA and mRNA data in three pathogenically distinct mouse models provided novel targets for the treatment of human HCC, bridging the translational gap between mouse data and human HCC. Our functional findings on the novel miR-107/Kif23 module provide important new insights into the control of mitosis in liver cancer cells. The findings that miR-107 overexpression or Kif23 inhibition had a dramatic functional effect on inhibiting the growth of liver cancer cellsin vitroandin vivosuggest that the miR-107/Kif23 axis may be a promising novel target and potential adjunct to sequential systemic therapy of HCC.Graphical abstractHighlightsmiR-107 is globally downregulated in mouse liver cancers of different etiologies and represents a potential biomarker in human HCC.Integration ofin-silico-prediction, miRNA and mRNA transcriptomics identified KIF23, a mitotic spindle-associated protein, as a specific target mediating the biological effects of miR-107.The miR-107/KIF23 module promotes replicative fitness of liver cancer cells through an essential function in cytokinesisMice receiving shRNA targeting Kif23 were completely protected from oncogene-induced liver cancer.

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Section: Discussionmentioning

confidence: 99%

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Castoldi,

Roy,

Lohr

et al. 2023

Preprint

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“…miR-107 belongs to a highly conserved miR-15/miR-107 gene family that shares a common “AGCAGC” sequence near the end of the mature miRNAs’ 5′UTR ( Finnerty et al, 2010 ). miR-107 is transcribed from the host gene PANK1 , which is broadly expressed in many tissues and has been implicated in cancers ( Turco et al, 2020 ), chemosensitivity ( Chen et al, 2021 ), ischemic stroke ( Yang et al, 2014 ), insulin resistance ( Yang et al, 2020 ), and neuronal differentiation ( Croizier et al, 2018 ). Dysregulation of miR-107 is associated with diverse pathways, including: obesity and diabetes ( Foley and O'Neill, 2012 ), Alzheimer’s disease ( Chang et al, 2017 ), cancers ( Turco et al, 2020 ; Chen et al, 2021 ), and drug treatment and environmental exposure ( Chou et al, 2017 ; Chen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…miR-107 is transcribed from the host gene PANK1 , which is broadly expressed in many tissues and has been implicated in cancers ( Turco et al, 2020 ), chemosensitivity ( Chen et al, 2021 ), ischemic stroke ( Yang et al, 2014 ), insulin resistance ( Yang et al, 2020 ), and neuronal differentiation ( Croizier et al, 2018 ). Dysregulation of miR-107 is associated with diverse pathways, including: obesity and diabetes ( Foley and O'Neill, 2012 ), Alzheimer’s disease ( Chang et al, 2017 ), cancers ( Turco et al, 2020 ; Chen et al, 2021 ), and drug treatment and environmental exposure ( Chou et al, 2017 ; Chen et al, 2020 ). In parallel, CYP substrate drug clearance and expression of the CYP enzymes also change in many of these events, such as obesity ( Brill et al, 2012 ), diabetes ( Darakjian et al, 2021 ), and cancers ( Fahy et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide microRNA profiles identify miR-107 as a top miRNA associating with expression of the CYP3As and other drug metabolizing cytochrome P450 enzymes in the liver

2022

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Cytochrome P450 (CYP) drug metabolizing enzymes are responsible for the metabolism of over 70% of currently used medications with the CYP3A family being the most important CYP enzymes in the liver. Large inter-person variability in expression/activity of the CYP3As greatly affects drug exposure and treatment outcomes, yet the cause of such variability remains elusive. Micro-RNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression and are involved in diverse cellular processes including metabolism of xenobiotics and therapeutic outcomes. Target prediction and in vitro functional assays have linked several miRNAs to the control of CYP3A4 expression. Yet, their co-expression with CYP3As in the liver remain unclear. In this study, we used genome-wide miRNA profiling in liver samples to identify miRNAs associated with the expression of the CYP3As. We identified and validated both miR-107 and miR-1260 as strongly associated with the expression of CYP3A4, CYP3A5, and CYP3A43. Moreover, we found associations between miR-107 and nine transcription factors (TFs) that regulate CYP3A expression, with estrogen receptor alpha (ESR1) having the largest effect size. Including ESR1 and the other TFs in the regression model either diminished or abolished the associations between miR-107 and the CYP3As, indicating that the role of miR-107 in CYP3A expression may be indirect and occur through these key TFs. Indeed, testing the other nine CYPs previously shown to be regulated by ESR1 identified similar miR-107 associations that were dependent on the exclusion of ESR1 and other key TFs in the regression model. In addition, we found significant differences in miRNA expression profiles in liver samples between race and sex. Together, our results identify miR-107 as a potential epigenetic regulator that is strongly associated with the expression of many CYPs, likely via impacting the CYP regulatory network controlled by ESR1 and other key TFs. Therefore, both genetic and epigenetic factors that alter the expression of miR-107 may have a broad influence on drug metabolism.

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“…These ndings show evidence that, HDACi-R cells are resistant to SAHA with increased cell viability compared to that of parental HA22T cells. miR-342-5p is a key regulator of cell survival in HDACi-R and HA22T cells microRNAs are important in tumor development and growth regulation [25]. The impact of miRNAs on HCC drug resistance was examined in HDACi-R and HA22T cell types and their differential miRNA expressions were determined using microarray analysis.…”

Section: Assessment Of Hdaci-r Cell Propertiesmentioning

confidence: 99%

Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR- 342-5p/CFL1

Nakka,

Jassi,

Chen

et al. 2023

Preprint

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Background Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. Methods MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. Results Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. Conclusion Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.

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Hsa-miR-107 regulates chemosensitivity and inhibits tumor growth in hepatocellular carcinoma cells

Cited by 16 publications

References 46 publications

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

KIF23 regulation by miR-107 controls replicative tumor cell fitness in mouse and human hepatocellular carcinoma

Genome-wide microRNA profiles identify miR-107 as a top miRNA associating with expression of the CYP3As and other drug metabolizing cytochrome P450 enzymes in the liver

Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR- 342-5p/CFL1

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