Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop

Abstract

Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/ STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5);

Novel peptide GX1 inhibits angiogenesis by specifically binding to transglutaminase-2 in the tumorous endothelial cells of gastric cancer

“…As described previously 28 , 29 , proteins in cell lysates were extracted using RIPA lysis buffer with the protease inhibitor (Roche, Catalog Number: 04693159001, Switzerland). Protein concentrations were measured using the BCA protein assay kit (Beyotime, Catalog Number: P0010, China) according to the manufacturer’s instructions.…”

“…The apoptosis of co-HUVECs was detected by FCM analysis as described 29 , 31 . The Annexin V-FITC apoptosis detection kit (BD Biosciences, Catalog Number: 556547, China) was used for apoptosis assays.…”

LINC02163 regulates growth and epithelial-to-mesenchymal transition phenotype via miR-593-3p/FOXK1 axis in gastric cancer cells

“…Gastric cancer (GC) is one of the most frequent malignant tumours and has highly invasive growth pattern [1]. GC often displays high rates of lymph node metastasis when diagnosed, which contributes to poor prognosis of the disease [2].…”

Protein Promiscuity in H2O2Signaling

“…A relationship between STAT3 and CypB has also been demonstrated in cancer cells, with STAT3 repressing transcription of CypB inhibitors, and CypB in turn promoting the activation of STAT3 (210). The parvulin family PPI, Pin1, specifically targets prolines adjacent to phosphorylated Ser/ Thr and makes a junction between PPIases and kinase pathways, whereas oxidation of its Cys113 to sulfenic/sulfinic acid inhibits its catalytic activity (46,149,411).…”