MicroRNA-495-3p inhibits multidrug resistance by modulating autophagy through GRP78/mTOR axis in gastric cancer

Abstract

Multidrug resistance (MDR) accounts for poor prognosis in gastric cancer (GC). MicroRNAs (miRNAs) are critical regulators of MDR via modulation of the target genes. The present study revealed that miR-495-3p could act via a target gene, GRP78, to regulate the process of autophagy and inhibit MDR. Based on the in vitro and in vivo gain-of-function or loss-of-function experiments, overexpression of miR-495-3p was sufficient to reverse the MDR to four chemotherapeutics in vitro and inhibit the tumor growth in vivo. Moreover, GRP78 was positively associated with the occurrence of autophagy. Thus, reducing the expression of GRP78 by siRNA resulted in autophagy-suppressive activity similar to that of miR-495-3p on mammalian target of rapamycin (mTOR) and its substrates activation and autophagy inhibition, while restoring GRP78 attenuated the anti-autophagy effects caused by miR-495-3p. Clinically, either miR-495-3p downregulation or GRP78 upregulation was associated with malignant phenotypes in patients with GC. In conclusion, these findings demonstrate that miR-495-3p is an important regulator of autophagy balance and MDR by modulating the GRP78/mTOR axis. In addition, miR-495-3p and GRP78 could be used as prognostic factors for overall survival in GC, which implicates miR-495-3p as a therapeutic target in cancer.

Tunicamycin promotes metastasis through upregulating endoplasmic reticulum stress induced GRP78 expression in thyroid carcinoma

“…Our previous research showed that GRP78 is overexpressed and correlated with invasion, metastasis and poor prognosis in esophageal squamous cell carcinoma (ESCC) patients [20]. Besides, the expression of GRP78 is shown to be signi cantly higher in multidrug resistance in gastric cancer cells and knockdown of GRP78 signi cantly reversed multidrug resistance in gastric cancer [21][22]. All these studies con rmed that GRP78 is involved in the pathological process of numerous cancers.…”

“…Recent molecular and pathological studies have reported that glucose-regulated protein (GRP78) is involved in tumor development and progression [16][17][18][19][20][21][22]. GRP78 (which is also known as HSPA5) is reported to be involved in ER stress and overexpression of many types of human cancers, such as hepatocellular carcinoma, esophageal cancer, gastric cancer and prostate cancer.…”

Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression

“…Accumulating evidence have validated that miRNAs are capable of regulating autophagy via affecting intracellular levels of key molecular proteins involved in the autophagic process . Recent study has demonstrated that miR‐495‐3p could inhibit autophagy in MDR GC cells by activating mTOR signaling and targeting GRP78 . Zhang et al indicated that miRNA‐218 inhibited GC MDR by de‐regulating expression of SMO in the Hedgehog/smoothened pathway .…”

“…169 Recent study has demonstrated that miR-495-3p could inhibit autophagy in MDR GC cells by activating mTOR signaling and targeting GRP78. 170 Zhang et al indicated that miRNA-218 inhibited GC MDR by de-regulating expression of SMO in the Hedgehog/smoothened pathway. 148 Moreover, Li et al validated that miRNA-148a-3p suppressed the cellular-protective autophagy in cisplatin-resistant GC cells by activating mTORC1 activity and inhibiting RAB12 expression.…”

The Complex Network between MYC Oncogene and microRNAs in Gastric Cancer: An Overview

“…In this process, total complementarity results in the cleavage of the mRNA target strand, while imperfect complementarity leads to repression of the mRNA translation [51]. Thus, unsurprisingly, miRNA deregulation has been described in different diseases, including GC [47,52], and this deregulation may help us elucidate critical pathways involved in carcinogenesis processes and identify potential prognostic or predictive biomarkers [53][54][55][56].…”