Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC.Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

Tumor microenvironment mediated by suppression of autophagic flux drives liver malignancy

“…In this study, autophagic suppression enhances the growth inhibition effect of miR-7 in HepG2 cells suggesting that modulation of autophagy could be practical approach to promoting onco-suppressive activity of miR-7. Our current study identified miR-135a as a highly expressed miRNA of tumor tissues in association with higher FVII/PAR2 expression and in response to FVII/PAR2 activation [81] . Interestingly, increased miR-135a levels in HCC are significantly associated with viral etiology, hepatitis B surface antigen (HBsAg), tumor staging, recurrence, microvascular invasion as well as decreased disease-free survival.…”

Prognostic significance of microRNA-135 in patients with digestive system cancers: a systematic review and meta-analysis

“…The 17 included studies were reports from around the world, including 14 from China [14,15,18,28,30,31,33,34,36–41], 1 from the U.K. [29], and 2 from Germany [32], all of which were published between 2012 and 2019. Among the included studies, five focused on CRC [14,29,30,35,37], four were on HCC [28,32,39,41], three were about gastric cancer [15,18,31], one was on ESCC [34], three were regarding PC [33,38,40], and one investigated gastric cardia adenocarcinoma (GCAC) [36]. There were 14 studies [14,15,18,28–31,33,34,36–38,40,41] involving 1225 patients that reported the OS, 7 [14,15,28,33,35,39,40] that reported DFS, and 2 [29,32] reported the RFS.…”

Non-coding RNAs open a new chapter in liver cancer treatment

“…This year, Teufel and coworkers have identified a plasmatic signature of nine miRNAs including miR-122 (miR-122, miR-30a, miR-125b, miR-200a, miR-374b, miR-15b, miR-107, miR-320, and miR-645), which is significantly associated with patient overall survival during regorafenib treatment [27]. In addition, miR-135a, a miRNA upregulated in HCC [28], has been also described as a promising prognostic factor [29], since its expression is associated with recurrence after tumor resection [30].…”