Complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma

Abstract

miRNAs play a crucial role in cancer development and progression. However, results on the impact of miRNAs on drug sensitivity and tumor biology vary, and most studies to date focussed on either increasing or decreasing miRNA expression levels. Therefore, the current study investigated the role of different expression levels of miR-130a-3p and miR-148a-3p on drug resistance and tumor biology in four esophageal squamous cell carcinoma cell lines. Interestingly, up- and downregulation of both miRNAs significantly increased sensitivity towards chemotherapy. MiRNA modulation also reduced adherence and migration potential, and increased apoptosis rates. Target analyses showed that up- and downregulation of both miRNAs activated the apoptotic p53-pathway via increased expression of either BAX (miR-148a-3p) or Caspase 9 (miR-130a-3p). miR-148a-3p downregulation seemed to mediate its effects primarily via regulation of Bim rather than Bcl-2 levels, whereas we found the opposite scenario following miR-148a-3p upregulation. A similar effect was observed for miR-130a-3p regulating Bcl-2 and XIAP. Our data provide the first evidence that miRNA modulation in both directions may lead to similar effects on chemotherapy response and tumor biology in esophageal squamous cell carcinoma. Most interestingly, up- and downregulation seem to mediate their effects via modulating the balance of several validated or predicted targets.

MicroRNA‐338‐5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id‐1

“…For example, gain of miR‐241‐3p expression enhanced sensitivity of ESCC cells to cisplatin, whereas loss of miR‐445‐3p had a similar effect . It was also reported that modulation of miR‐130a‐3p and miR‐148a‐3p in both directions increased the sensitivity of ESCC cells to 5‐FU and cisplatin . We found that ectopic overexpression of miR‐377, which targeted CD133 and suppressed cancer stemness, had a chemosensitizing effect on ESCC cells .…”

“…Despite 5‐FU being an antimetabolic agent widely used in treating gastrointestinal cancers, the response rate of esophageal carcinoma to 5‐FU is only 15% . Emerging evidence indicates that miRNAs are associated with chemoresistance, but relatively few miRNAs were experimentally validated to have the ability to regulate the sensitivity of ESCC cells to 5‐FU treatment . Our present study found that miR‐338‐5p was underexpressed in 5‐FU‐resistant ESCC cells, and that ectopic overexpression of miR‐338‐5p in these cells could increase their sensitivity to 5‐FU treatment both in vitro and in vivo.…”

Emerging Role of Non-Coding RNAs in Esophageal Squamous Cell Carcinoma

“…A previous report showed that Spatholobi Caulis tannin mediates several related circRNAs to suppress cell proliferation and promote apoptosis in cervical cancer [32]. In ESCC, ncRNAs have been suggested to play roles as oncogenes or tumor suppressors to regulate ESCC proliferation, apoptosis, epithelial-mesenchymal transition (EMT), metastasis, chemotherapy, or radiotherapy [33][34][35][36][37]. Additionally, several ncRNAs have been observed to serve as prognostic markers in patients with ESCC [5,38].…”

“…However, when miR-148a-3p was downregulated, BIM was observed to be noticeably upregulated compared to the upregulation of BCL2. Furthermore, miR-130a-3p showed similar regulatory effects for BCL2 and X-linked inhibitor of apoptosis protein (XIAP) [34]. Balancing the regulation of several target genes is critical for an efficient response of miRNAs towards chemotherapy in ESCC.…”

“…In vitro studies on the function of ncRNAs in ESCC are generally based on overexpression or knockdown of an ncRNA in ESCC cell lines. Overexpression plasmid or small interfering miRNA mimics and inhibitors are commonly used for transient overexpression or knockdown of miRNAs in ESCC cells [34,52,107]. RNA interference (RNAi), mainly involving siRNA and short hairpin RNA (shRNA), has been widely applied in knockdown of ncRNAs in ESCC cells [18,27,31,80].…”