Downregulation of leucine‐rich repeats and immunoglobulin‐like domains 1 by microRNA‐20a modulates gastric cancer multidrug resistance

Abstract

Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine‐rich repeats and immunoglobulin‐like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemosensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that upregulation of LRIG1 enhanced chemosensitivity in GC cells. Interestingly, miR‐20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3′ untranslated region. We also found that inhibition of miR‐20a suppressed GC MDR, and upregulation showed opposite effects. Moreover, we demonstrated that the miR‐20a/LRIG1 axis regulated GC cell MDR through epidermal growth factor receptor (EGFR)‐mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR‐20a and EGFR. Taken together, the newly identified miR‐20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemoresistance.

MiR‐876‐3p regulates cisplatin resistance and stem cell‐like properties of gastric cancer cells by targeting TMED3

“…Hence, identifying therapeutic targets is very helpful to GC treatment. Increasing evidence shows that miRNAs exert big effects on the occurrence, development, and drug resistance of GC . This study proved that miR‐876‐3p was downregulated in GC tissue samples in comparison with the corresponding normal tissues.…”

“…Increasing evidence shows that miRNAs exert big effects on the occurrence, development, and drug resistance of GC. 9,10,24 This study proved that miR-876-3p was downregulated in GC tissue samples in comparison with the corresponding normal tissues. Additionally, miR-876-3p expression was inhibited in GC samples of cisplatinresistant patients compared with GC samples of cisplatin-sensitive patients.…”

A microRNA-4516 inhibitor sensitizes chemo-resistant gastric cancer cells to chemotherapy by upregulating ING4

“…7 Some experiments have shown that certain miRNAs, including miR-25, miR-20a, and miR-623 are associated with a poor prognosis of cancer and have been reported to be signicantly upregulated in recurrent gastric carcinoma. [8][9][10][11][12] Therefore, we hypothesized that gastric cancer resistance may be related to abnormal expression of miRNAs. In addition, a lot of evidence has revealed that miRNA is involved in gastric cancer initiation and progression, including MDR.…”

Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis

“…43 Loss of LRIG1 expression has been confirmed in human GC lesions, whereas EGFR expression is significantly increased, which indicates that LRIG1 down-regulation might accelerate carcinogenesis through EGFR activation. Recently, Zhou et al 44 reported that EGFR down-regulation through LRIG1 inhibition by miR-20a affected apoptosis in the GC cell line SGC7901 with respect to the mitogen-activated protein kinase/ERK and phosphoinositide 3-kinase/AKT pathways, affecting the multidrug-resistance process. A similar study reported that the regulation of LRIG1 expression by miR-19a affected glioma cell growth.…”