miR-20a induces cisplatin resistance of a human gastric cancer cell line via targeting CYLD

Abstract

The dysregulation of microRNAs (miRNAs) has been demonstrated to contribute to drug resistance of cancer cells, and sustained nuclear factor (NF)κB activation is also pivotal in tumor resistance to chemotherapy. In the present study, an essential role for miRNA (miR)-20a was identified in the regulation of gastric cancer (GC) chemoresistance. The expression level of miR‑20a was assayed by reverse transcription‑quantitative polymerase chain reaction. Additionally, 3-(4,5-dimethylthiazol-2‑yl)-2,5-diphenyltetrazolium bromide was used to detect the drug‑resistance phenotype changes of cancer cells associated with upregulation or downregulation of miR‑20a. Protein expression levelss were measured by western blotting and immunohistochemistry. Flow cytometry was used to detect cisplatin‑induced apoptosis. It was found that miR‑20a was markedly upregulated in GC plasma and tissue samples. Additionally, miR‑20a was upregulated in GC plasma and tissues from patients with cisplatin (DDP) resistance, and in the DPP‑resistant gastric cancer cell line (SGC7901/DDP). The expression of miR‑20a was inversely correlated with the expression of cylindromatosis (CYLD). Subsequently, the assessment of luciferase activity verified that CYLD was a direct target gene of miR‑20a. Treatment with miR‑20a inhibitor increased the protein expression of CYLD, downregulated the expression levels of p65, livin and survivin, and led to a higher proportion of apoptotic cells in the SGC7901/DDP cells. By contrast, ectopic expression of miR‑20a significantly repressed the expression of CYLD, upregulated the expression levels of p65, livin and survivin, and resulted in a decrease in the apoptosis induced by DDP in the SGC7901 cells. Taken together, the results of the present study suggested that miR‑20a directly repressed the expression of CYLD, leading to activation of the NFκB pathway and the downstream targets, livin and survivin, which potentially induced GC chemoresistance. Altering miR‑20a expression may be a potential therapeutic strategy for the treatment of chemoresistance in GC in the future.

Livin enhances chemoresistance in head and neck squamous cell carcinoma

“…Therefore, in the present study, we investigated the role of Livin in determining susceptibility to commonly used chemotherapeutic drugs, such as docetaxel, cisplatin and 5-FU, in human HNSCC cell lines. Although several studies have described that Livin contribute to the resistance of various chemotherapeutic drugs including cisplatin in various cancers (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), the present study is the first to demonstrate the correlation between Livin and chemoresistance in human HNSCC.…”

“…Livin, a recently discovered IAP, is composed of a single BIR domain and a RING motif (9). Livin has been implicated in chemoresistance in various cancers (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). It has been reported to play a role in resistance to cisplatin in bladder cancer, renal carcinoma, gastic cancer, hepatocellular carcinoma, lung adenocarcinoma/ non-small cell carcinoma, osteosarcoma, colon cancer and ovarian carcinoma (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)31).…”

“…Zhu et al (22) demonstrated that miRNA-20a induces cisplatin resistance via targeting cylindromatosis (CYLD), leading to activation of nuclear factor (NF)-κB and downstream target Livin in gastric cancer. Activation of NF-κB pathway and downstream target Livin by SHANK-associated RH domain interacting protein (SHARPIN) contributed to docetaxel resistance in prostate cancer (34).…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…Moreover, Zhou et al established that miR-20a expression in glioma cells was negatively correlated to Temozolomide sensitivity by targeting DNA methyltransferase (DNMT1) (286). In gastric cancer, miR-20a negatively regulates cylindromatosis (CYLD) expression, thus inducing cisplatin resistance (287). miR-15b had a dual role in oral tongue squamous cell carcinoma (TSCC) and lung adenocarcinoma; through the regulation of TRIM14 it was implicated in the reversion of cisplatin resistance in TSCC (288), while it decreased sensitivity to cisplatin by targeting PEBP4 in lung adenocarcinoma (289).…”

The correlation of circulating pro‐angiogenic miRNAs’ expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer

“…MiR‐18a, another pro‐angiogenic miRNA, is also discovered to be increased in several cancers including breast cancer, esophageal squamous cell carcinoma, and colorectal carcinoma, and it induces cancer cells’ proliferation, invasion, and autophagy through regulating PTEN‐PI3K‐AKT‐mTOR signaling axis and Dicer 32, 38, 39. miR‐20a is also regarded as an oncogene in several cancers such as cervical cancer, non‐small cell lung cancer, and anaplastic thyroid cancer, which raised cancer cells’ proliferation, invasion, and spheroid formation (stem cell ability) via targeting multiple genes including CYLD, ATG7, TIMP2, and LIMK1 40, 41, 42, 43. In addition, miR‐210, which leads to angiogenesis through stimulating VEGF production, is also discovered to be increased in several cancers, which correlates with higher pathological grade and elevated TNM stages, and it acts as an carcinogenic miRNA by stimulating cancer cells’ proliferation, migration, and invasion 17, 44, 45, 46, 47, 48.…”