miR‑21‑5p confers doxorubicin resistance in gastric cancer cells by targeting PTEN and TIMP3

Abstract

Drug resistance and disease recurrence are major obstacles to the effective treatment of cancer, including gastric cancer (GC). However, the mechanisms of drug resistance remain to be fully elucidated. The present study investigated the roles of microRNA (miR)-21-5p in the doxorubicin (DOX) resistance of GC cells and the underlying mechanisms. miR-21-5p expression levels were identified to be inversely correlated with two well-known tumor suppressor genes, phosphatase and tensin homologue and tissue inhibitor of matrix metalloproteinases 3, and were upregulated in GC cell lines in proportion to their degree of resistance. Suppressing miR-21-5p expression partially sensitized SGC7901/DOX cells to DOX, suggesting that knockdown of miR-21-5p expression may be used as a therapeutic strategy to improve GC cell resistance. Importantly, increased miR-21-5p expression levels at diagnosis were correlated with clinicopathological characteristics including advanced stage and poor prognosis, further implying that a relapse of GC may be a consequence of miR-21-5p upregulation, thus providing evidence for the potential utility of miR-21-5p antagonism to sensitize GC cells to DOX chemotherapy.

Noncoding RNAs in gastric cancer: implications for drug resistance

“…MiR-20a was also proved to enhance gastric cancer resistance to ADR via inhibiting expression of early growth response 2 (EGR2), a member of a multi-gene family which encoding C2H2type zinc-finger proteins [60]. Through silencing PTEN and tissue inhibitor of matrix metalloproteinases 3 (TIMP3), miR-21-5p increases ADR resistance of gastric cancer cells [61]. It has also been found that miR-633 promotes ADR resistance of gastric cancer by inhibiting expression of Fas-associated death domain (FADD) [62].…”

Integration of miRNA‐regulatory networks in hepatic stellate cells identifies TIMP3 as a key factor in chronic liver disease

“…In line with this common regulation, TIMP3 and PTEN were both implicated in miR-221/miR-222-mediated TRAIL resistance 41 and miR-21-5p-mediated doxorubicin resistance. 42 The critical role of PTEN in chronic liver diseases was recently demonstrated in vivo with Pten-null mice being more prone to develop progressive liver fibrosis and HSC activation than their wild type littermates. 43 In addition, PTEN The National Cancer Institute proliferation subtype (NCIP, low and high proliferation).…”

<p>Research Progress in microRNA-Based Therapy for Gastric Cancer</p>

“…Increased expression levels of miR-494, miR-422a, miR-140, miR-103/107, and miR-16-1, and reduced levels of miR-501-5p and miR-21-5p promoted the chemosensitivity to DOX (for more details, refer to Table 3). [57][58][59][60][61][62][63][64] Among these, miR-103 and miR-107 were the only miRNAs demonstrated to have effects on resistance both in vitro and in vivo. 60 Another important miRNA that is taking the spotlight in chemotherapy resistance research is miR-21.…”

“…miR-21-5p targets PTEN to induce both DOX and DDP resistance. 30,48,64 Other studies showed that miR-21 targets P-gp to induce PTX resistance. 65 Notably, PTEN is not only a target gene of miR-21-5p but is also a target of miR-193-3p, miR-147, and miR-106a.…”

“…21,22,46 Through targeting PTEN, miRNAs regulate 5-FU, DDP, and DOX resistance in GC. 21,22,30,46,48,64 Hence, we speculated that miR-21-5p and its target gene PTEN may play essential and broad roles in regulating drug resistance in GC.…”