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

Abstract

Background and Aim Gastric cancer (GC), a prevalent tumor, exerts a major economic burden, and we aimed to explore miR‐876‐3p's effects on GC and related mechanisms. Methods Cell viability was analyzed via CCK‐8 and colony formation assay. Stem cell‐like properties were examined via spheroid colony formation assay. mRNA abundance of key genes was analyzed via quantitative polymerase chain reaction. Protein level of TMED3 and stem cell markers was examined by western blot. TargetScan, luciferase, and biotin‐miRNA pulldown assay were used to identify miR‐876‐3p's target. Results MiR‐876‐3p was downregulated in GC, and its mRNA level had negative relationship with cisplatin resistance of GC. Moreover, decreased miR‐876‐3p expression level suggested poor prognosis of GC patients. MiR‐876‐3p inhibited drug resistance of cisplatin‐resistant cell line SGC‐7901/DDP and MKN‐45/DDP, as shown by decreased cell viability, IC50, and colony formation ability. MiR‐876‐3p inhibited stem cell‐like features and downregulated the expressions of Sox‐2, Oct‐4, CD133, and CD44 in GC cells. Luciferase and biotin‐miRNA pulldown assay confirmed that TMED3 was miR‐876‐3p's direct target. TMED3 siRNA inhibited miR‐876‐3p's effects on cisplatin resistance and stem cell‐like features of SGC‐7901/DDP cells. Conclusion MiR‐876‐3p enhanced cisplatin sensitivity and restricted stem cell‐like features of GC through targeting TMED3.

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

“…Cancer stem cells (CSCs) contributed to metastasis, recurrence and drug resistance in cancers [11][12][13][14], and previous data suggested that CSCs enrichment contributed to cisplatin-resistance in GC cells [17,18]. Therefore, elimination of CSCs will help to improve chemo-sensitivity in GC cells [19].…”

“…Cancer stem cells (CSCs) were a subgroup of cancer cells characterized by high self-renewal abilities [11,12], which sustained the heterogeneity of tumor cells and contributed to metastasis and bad prognosis in GC patients [13,14]. In addition, recent data indicated that CSCs were pivotal for sustaining cisplatinresistance in multiple cancers, such as head and neck squamous cell carcinoma (HNSCC) [15], lung cancer [16] and GC [17,18]. Speci cally, Peng C et al found that restriction of CSCs features enhanced cisplatin sensitivity [17], and Zhang L et al validated that induction of CSCs properties increased cisplatin-resistance in GC cells [18], which suggested that elimination of CSCs was an ideal strategy to improve cisplatin-sensitivity in GC [19].…”

“…In addition, recent data indicated that CSCs were pivotal for sustaining cisplatinresistance in multiple cancers, such as head and neck squamous cell carcinoma (HNSCC) [15], lung cancer [16] and GC [17,18]. Speci cally, Peng C et al found that restriction of CSCs features enhanced cisplatin sensitivity [17], and Zhang L et al validated that induction of CSCs properties increased cisplatin-resistance in GC cells [18], which suggested that elimination of CSCs was an ideal strategy to improve cisplatin-sensitivity in GC [19]. By conducting the preliminary experiments, we surprisingly found that low-dose DB regulated CSCs properties in GC cells, however, up until now, no existed literatures reported the link between DB and cell stemness.…”

Noncoding RNAs in gastric cancer: implications for drug resistance

“…Similarly, tumor suppressor miR-362-5p, miR-198, miR-574-3p, miR-876-3p, miR-874 and let-7b have been reported to reverse DDP resistance of gastric cancer cells via silencing suppressor of zeste 12 protein (SUZ12), fibroblast growth factor receptor 1 (FGFR1), zinc finger E-box binding homeobox transcription factor 1 (ZEB1), TMED3, autophagy-related 16-like 1 (ATG16 L1) and AURKB, respectively [117][118][119][120][121][122]. In addition, via targeting excision repair cross-complementing (ERCC), exogenous over-expression of tumor suppressor miR-122, miR-138-5p and miR-192-5p could also reverse DDP resistance of gastric cancer [48,123,124].…”

DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ

“…Cancer stem cells (CSCs) are a kind of cancer cells with typical stem cell features, such as malignant development, self‐renewal, metastasis and chemoresistance and exert ability to initiate tumour growth [6] . It has been reported that CSCs make up the tumour bulk due to the abundant differentiated progeny [7] .…”