<p>The miRNA, miR-125b, Inhibited Invasion and Metastasis of Gastric-Cancer Cells by Triggering the STAT3 Signaling Pathway</p>

Abstract

Objective To investigate the function and the mechanism of miR-125b in the invasion and metastasis of gastric cancer and provide experimental basis for finding and developing new therapeutic strategies for gastric cancer. Methods The difference of miR-125b expression in gastric cancer tissues and adjacent tissues was detected by qRT-PCR. The same test was performed in different gastric cancer cell lines. The effect of miR-125b on SGC-7901 and BGC-823 gastric cancer cell viability was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Transwell assay was used to detect the effect of miR-125b on invasion and metastasis of gastric cancer cells. The target gene STAT3 of miR-125b was identified and validated by dual luciferase reporter assay. Western blot assay and immunofluorescence staining were used to detect the effect of miR-125b on the expression and distribution of STAT3 protein. The inhibitor and activator of STAT3 were used to confirm the effect of STAT3 on invasion and metastasis of gastric cancer cells. Peritoneal metastasis experiment and IHC were used to study the inhibitory effect of miR-125b on the metastasis of gastric cancer in vivo. Results The results of qRT-PCR showed that 125b expression was significantly lower in gastric cancer than in adjacent tissues, which indicated poor prognosis for gastric-cancer patients. Furthermore, two gastric-cancer cell lines, SGC-7901 and BGC-823, exhibited lower miR-125b levels than the normal cell line HEK293. After treatment with miR-125b mimics, cell proliferation was markedly inhibited. Meanwhile, the invasion and metastasis of gastric cancer cells were also inhibited after treated with miR-125b mimics. We also identified the signal transducer and activator of transcription 3 (STAT3) as a potential target of miR-125b based on patient data from The Cancer Genome Atlas (TCGA). Dual luciferase assays revealed that miR-125b directly inhibited STAT3 by binding to its 3′-untranslated region (UTR). Immunofluorescence assay showed that miR-125b could affect the subcellular distribution of STAT3. Moreover, treatment with miR-125b mimics or stattic inhibited invasion and migration in the gastric cancer cell lines, and IL-6 could reverse the inhibitory effect. Finally, nude mice xenografted with gastric-cancer cells expressing miR-125b mimics exhibited smaller tumors and lower transfer rates than mice engrafted with control group cells. Conclusion These data suggested that miR-125b inhibited invasion and metastasis in gastric cancer by inhibiting STAT3; therefore, miR-125b and STAT3 could be potential therapeutic targets in the treatment of gastric cancer.

Dual STAT‑3 and IL‑6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL‑6/IL‑6R/STAT‑3 axis

“…The same effect has been observed with Stt in BTIC glioblastoma cells ( 65 ); activation of STAT-3 induces upregulation of c-Myc, Cyclin D1 and Bcl-xL and protects against apoptosis to promote cell survival and proliferation ( 66 ). Other studies have shown that Stt and Napabucasin (a small molecule that targets STAT-3) decrease cell renewal potential and the number of colonies, thus preventing metastasis into bone tissue of PCa in a mouse model ( 67 ) also, Terphenylin suppress the tumor growth and metastasis in mouse model of gastric cancer ( 68 ) In addition, STAT-3 inhibition via galiellalactone decreases formation of metastatic, clonogenic and spherical stem PCa and gastric cancer cells ( 69 , 70 ). Androgen deprivation contributes to development of CRPC in patients ( 71 ).…”

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response

“…The tumorsuppressor activity of miR-125 was found to be mediated through its interaction with 3′UTR of STAT3 mRNA. 165 The above-indicated studies highlighted that the STAT3 pathway can be either modulated by miRNAs by directly interacting with STAT3 transcripts or by modulating the expression of endogenous inhibitors of STAT3 signaling such as SOCS3 to promote/regress GC progression.…”