miR-338-3p inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma cells

Abstract

Down-regulation of the miRNA miR-338-3p correlates with the invasive ability of hepatocellular carcinoma (HCC) cells. However, it is currently unclear whether down-regulation of miR-338-3p induces epithelial-mesenchymal transition (EMT), which may be the underlying mechanism governing HCC invasion. Here, we demonstrate that restoration of miR-338-3p expression via transfection of a miR-338-3p mimic reversed EMT and inhibited the motility and invasiveness of HCC cells. Conversely, silencing of endogenous miR-338-3p expression with a miR-338-3p-specific inhibitor induced EMT and enhanced HCC cell motility. Additionally, Snail1 (an upstream regulatory protein of EMT) and Gli1 (a key transcription factor in the sonic hedgehog (SHH) signaling pathway) expression was up-regulated in cells treated with the miR-338-3p inhibitor and down-regulated by the miR-338-3p mimic. Further analyses demonstrated that miR-338-3p inhibitor-induced EMT in HCC cells was blocked by treatment with a small interfering RNA (siRNA) targeting Snail1, that the SHH signaling pathway was required for both miR-338-3p inhibitor-induced EMT and up-regulation of Snail1, and that miR-338-3p targeted a sequence within the 3′-untranslated region of N-cadherin mRNA. Notably, miR-338-3p expression was significantly down-regulated in HCC samples from patients with metastases and was associated with poor metastasis-free survival rates. Lastly, correlations between the expression levels of miR-338-3p and E-cadherin, Smoothened (SMO), Gli1, Snail1, N-cadherin, and vimentin were confirmed in HCC xenograft tumors and HCC patient specimens. Our findings suggest that miR-338-3p suppresses EMT and metastasis via both inhibition of the SHH/Gli1 pathway and direct binding of N-cadherin. miR-338-3p is a potential therapeutic target for metastatic HCC.

Mesenchyme modulates three-dimensional, collective cell migration of liver cellsin vitro- a role for TGFß pathway

“…Transwell assays can be considered a 3D single cell migration assay, but don't account for all the types of CCM that occur in biology. Using this approach, scientists have demonstrated various factors that control 2D HCC migration including TGFß1 (Fransvea, Angelotti et al 2008); (Ng, Tung-Ping Poon et al 2013), c-Myc (Zhao, Jian et al 2013), YAP (Fitamant, Kottakis et al 2015), goosecoid (Xue, Ge et al 2014), actopaxin (Biname, Lassus et al 2008), and more recently, miRNAs (miRNA-135a (Zeng, Liang et al 2016), miRNA-338-3p (Chen, Liang et al 2017), miRNA-1301 (Yang, Xu et al 2017), mir-665 (Hu, Yang et al 2018)). Thus, 3D murine migration during liver organogenesis, and 2D modeling in HCC have thus far provided potential molecular mechanisms driving or inhibiting liver 3D CCM.…”

Polymorphisms and expression pattern of circular RNA circ-ITCH contributes to the carcinogenesis of hepatocellular carcinoma

“…While the data for the estimated new cases and deaths for HCC in USA was 39,230 and 27,170, respectively [ 7 ]. Although many potential risk factors have been explored for their associations with susceptibility of HCC, the etiological factors and pathogenesis mechanisms underlying HCC development appear to be complex and heterogeneous [ 3 , 8 – 13 ].…”

Peer Review #1 of "Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma (v0.2)"

“…(Chen et al 2019;Huang et al 2017;Wang et al 2019;Zheng et al 2019) For example, SNHG3 sponged miRNA-151a-3p (Zheng et al 2019) andmiR-196a-5p (Chen et al 2019) in order to promote cell growth, invasion, and migration in osteosarcoma. miR-338-3p is downregulated in HCC and inhibits its progression in various ways including suppressing cell proliferation (Fu et al 2012), countering Warburg effects (Nie et al 2015) as well as inhibiting metastasis (Chen et al 2017;Zhang et al 2016d). A diverse array of molecules, such as mineralocorticoid receptors (Nie et al 2015), hepatitis B virus X (Fu et al 2012) and circular RNAs (circRNA) (Li et al 2019) have been validated as the direct upstream regulators of miR-338-3p in HCC.…”

“…A novel mechanism indicating that miR-338-3p expression might be regulated by lncRNA SNHG3 has been identified. The downstream binding targets of miR-338-3p, including N-cadherin (Chen et al 2017), MACC1 (Zhang et al 2016d), HIF-1α (Xu et al 2014), and CyclinD1 (Fu et al 2012) have also been well studied in HCC. However, for the first time, this study has predicted ZWINT as a potential target of miR-338-3p.…”