Regulation of CD44v6 expression in gastric carcinoma by the IL-6/STAT3 signaling pathway and its clinical significance

Abstract

As a cancer stem cell marker, CD44 variant 6 (CD44v6) has been implicated in carcinogenesis, tumor progression, and metastasis in a variety of human carcinomas. However, little is known about the expression of CD44v6 in Gastric Carcinoma (GC). Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.In this study, we systemically investigated CD44v6 expression by immunohistochemistry in normal, premalignant gastric mucosa (low and high grade intraepithelial neoplasia), and GC at various stages. The correlation of CD44v6 expression with clinicopathological characteristics, and prognosis in GC was also analyzed. Next, we investigated cell proliferation, migration and invasion in GC cell lines. Furthermore, we explored a novel mechanism by which CD44V6 was upregulated in GC cell.The immunohistochemistry results showed that enhanced expression of CD44v6 was closely associated with tumor differentiation, lymph node metastasis, TNM stage and poor prognosis in GC patients. In gastric cancer cell lines, CD44v6 involved in cell proliferation, invasion and metastasis in Next, report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD44v6. RNA interference silencing of STAT3 resulted in decrease of CD44v6 levels. We also found that STAT3 inhibitor AG490 decrease expression of CD44v6 by blocking activation of STAT3, even in the presence of IL-6. Targeting STAT3-mediated CD44v6 up-regulation may represent a novel, effective treatment by eradicating the stomach tumor microenvironment.

Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

“…The present study hypothesized that the STAT3 and COX-2 signaling pathways may be involved in the effects of exogenous H 2 S on the growth of PLC/PRF/5 cells. In order to corroborate our hypothesis, PLC/PRF/5 cells were co-treated with NaHS and AG490 (an inhibitor of STAT3) (36) or NS-398. Our data revealed that co-treatment of PLC/PRF/5 cells with NaHS and AG490 or NS-398 markedly alleviated the NaHS-induced cell growth effects, including proliferation, angiogenesis, migration and anti-apoptosis.…”

CD44v6 increases gastric cancer malignant phenotype by modulating adipose stromal cell-mediated ECM remodeling

“…6,45 Nevertheless, the relationship between CD44v6 overexpression and the clinicopathological features of GC remains unknown. To unravel whether CD44v6 expression by tumor cells affects the desmoplastic reaction and tumor growth of GC, we used an isogenic human GC cell line over-expressing the CD44v6 isoform (CD44v6 cells), previously established by our group (unpublished data).…”

“…4,5 Moreover, limited insights exist regarding the correlation between CD44 protein expression and clinicopathological features of GC. 6 …”

CD44v6 expression is a novel predictive marker of therapy response and poor prognosis in gastric cancer patients

“…Importantly, this occurs independently of TNM staging (Appendix Fig 9A-D), as demonstrated by multivariate analysis. Studies so far reporting an association between CD44v6 expression and worse GC patient survival, 18,19 enclosed low patients' number and failed to demonstrate prognostic value for CD44v6 expression independently of TNM staging. Our study addresses this issue in the largest GC patient cohort tested so far, and demonstrates that CD44v6 is truly an independent marker of poor prognosis, as it has been described for colorectal cancer.…”

“…13 Recently, two reports showed a positive association between increased expression of CD44v6 and worse OS in GC patients. 18,19 However, both studies showed a positive correlation between CD44v6 expression and higher TNM staging, leaving reasonable doubt as to whether CD44v6 tumor expression is an independent factor of poor prognosis in GC. In addition, most articles published on CD44v6 in GC cohorts included a limited number of patients, making it difficult to obtain statistically significant results.…”