Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF

PLOS ONE, Dec 2019

Background Studies have been shown that miR-125a plays an important role in carcinogenesis, however, the role of miR-125a in hepatocellular carcinoma (HCC) remains elusive. Methodology/Principal Real time-PCR (qRT-PCR) was performed to test the significance of miR-125a in HCC. Ectopic expression of miR-125a was used to test the influences of miR-125a on proliferation and metastasis of HCC cells in vitro and in vivo. Predicted target genes of miR-125a were determined by dual-luciferase reporting, qRT-PCR, and western blot (WB) analyses. Then immunohistochemical staining (IHC) was used to detect the expression of target genes, and the correlations and prognostic values of miR-125a and its target genes were also investigated. Conclusions/Significance Decreased miR-125a was observed in both HCC tissues and cell lines, and associated with patients’ aggressive pathologic features. Up-regulating miR-125a significantly inhibited the malignant phenotypes by repressing the expression of matrix metalloproteinase 11 (MMP11) and vascular endothelial growth factor A (VEGF-A) both in vitro and in vivo. Furthermore, miR-125a expression was inversely correlated with both MMP11 and VEGF-A expression in HCC tissues. Inhibiting miR-125a could increase both MMP11 and VEGF-A expression, and RNA interference targeting MMP11 or VEGF-A mRNA could rescue the loss of miR-125a functions. MiR-125a inhibits the proliferation and metastasis of HCC by targeting MMP11 and VEGF-A. Up-regulation of miR-125a might be a promising approach and a prognostic marker for HCC.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0040169&type=printable

Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF

et al. (2012) Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF. PLoS ONE 7(6): e40169. doi:10.1371/journal.pone.0040169 Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF Daiming Fan 0 Qian Bi 0 Shanhong Tang 0 Lin Xia 0 Rui Du 0 Rui Fan 0 Liucun Gao 0 Jiang Jin 0 Shuhui Liang 0 Zheng Chen 0 Guanghui Xu 0 Yongzhan Nie 0 Kaichun Wu 0 Jie Liu 0 Yongquan Shi 0 Jie Ding 0 Chun-Ming Wong, University of Hong Kong, Hong Kong 0 1 State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University , Xi'an , P.R. China , 2 Department of Digestive Diseases, Huashan Hospital, Fudan University , Shanghai , China Background: Studies have been shown that miR-125a plays an important role in carcinogenesis, however, the role of miR125a in hepatocellular carcinoma (HCC) remains elusive. Methodology/Principal: Real time-PCR (qRT-PCR) was performed to test the significance of miR-125a in HCC. Ectopic expression of miR-125a was used to test the influences of miR-125a on proliferation and metastasis of HCC cells in vitro and in vivo. Predicted target genes of miR-125a were determined by dual-luciferase reporting, qRT-PCR, and western blot (WB) analyses. Then immunohistochemical staining (IHC) was used to detect the expression of target genes, and the correlations and prognostic values of miR-125a and its target genes were also investigated. Conclusions/Significance: Decreased miR-125a was observed in both HCC tissues and cell lines, and associated with patients' aggressive pathologic features. Up-regulating miR-125a significantly inhibited the malignant phenotypes by repressing the expression of matrix metalloproteinase 11 (MMP11) and vascular endothelial growth factor A (VEGF-A) both in vitro and in vivo. Furthermore, miR-125a expression was inversely correlated with both MMP11 and VEGF-A expression in HCC tissues. Inhibiting miR-125a could increase both MMP11 and VEGF-A expression, and RNA interference targeting MMP11 or VEGF-A mRNA could rescue the loss of miR-125a functions. MiR-125a inhibits the proliferation and metastasis of HCC by targeting MMP11 and VEGF-A. Up-regulation of miR-125a might be a promising approach and a prognostic marker for HCC. - Funding: This work was supported by National Basic Research Program of China (No. 2010CB732400) and National Natural Science Foundation of China (No. 30973428, 30900674 and 30970149). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Hepatocellular carcinoma (HCC) is the second most frequent cause of cancer death worldwide, and half of HCC diagnoses and deaths were estimated to occur in China [1]. Despite improvements in surgery and other treatments, the postoperative prognosis of HCC patients is still unsatisfactory due to the high rate of recurrence and metastasis. Therefore, identifying the malignant factors and understanding the mechanisms are critical for the improvement of therapeutic strategies for HCC patients. MicroRNAs (miRNAs) are small non-protein-coding RNAs of 2024 nucleotides that can down-regulate the expression of their target genes through binding to the 39 untranslated regions (UTRs) of target mRNAs, resulting in mRNA degradation and translation inhibition [2,3]. Several miRNAs have been identified to be abnormally expressed, and to be associated with the malignant progressions of various human cancers [4,5,6]. MiRNAs were recently found to be frequently down-regulated in HCC, and they were also shown to be associated with the carcinogenesis, metastasis, recurrence and prognosis of HCC [7,8,9,10]. However, further investigation is needed to define the molecular mechanisms underlying the effects of miRNAs on the development of HCC. Previous studies have demonstrated that several miRNAs that are located in fragile sites or aberrant genomic regions play oncogenic or suppressive roles in the progression of human cancers [4]. MiR-125a is located at 19q13, which is frequently deleted in several human cancers. MiR-125a over-expression impaired the anchorage-dependent growth, migration and invasion of breast cancer cells by down-regulating ERBB2 and ERBB3 in the ERBB2-dependent SKBR3 cell line [11]. Researchers showed that miR-125a could inhibit the proliferation of human gastric cancer cells in combination with trastuzumab [12]. Furthermore, miR-125a was also downregulated in non-small cell lung cancer and had inverse effects on the invasion and migration of lung cancer cells [13]. Overexpression of miR-125a induces conversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial morphology, suggesting that miR-125a is a negative (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0040169&type=printable

Qian Bi, Shanhong Tang, Lin Xia, Rui Du, Rui Fan, Liucun Gao, Jiang Jin, Shuhui Liang, Zheng Chen, Guanghui Xu, Yongzhan Nie, Kaichun Wu, Jie Liu, Yongquan Shi, Jie Ding, Daiming Fan. Ectopic Expression of MiR-125a Inhibits the Proliferation and Metastasis of Hepatocellular Carcinoma by Targeting MMP11 and VEGF, PLOS ONE, 2012, Volume 7, Issue 6, DOI: 10.1371/journal.pone.0040169