IL-26 Promotes the Proliferation and Survival of Human Gastric Cancer Cells by Regulating the Balance of STAT1 and STAT3 Activation

Abstract

Interleukin-26 (IL-26) is one of the cytokines secreted by Th17 cells whose role in human tumors remains unknown. Here, we investigated the expression and potential role of IL-26 in human gastric cancer (GC). The expression of IL-26 and related molecules such as IL-20R1, STAT1 and STAT3 was examined by real-time PCR and immunohistochemisty. The effects of IL-26 on cell proliferation and cisplatin-induced apoptosis were analyzed by BrdU cooperation assay and PI-Annexin V co-staining, respectively. Lentiviral mediated siRNA was used to explore its mechanism of action, and IL-26 related signaling was analyzed by western blotting. Human GC tissues showed increased levels of IL-26 and its related molecules and activation of STAT3 signaling, whereas STAT1 activation did not differ significantly between GC and normal gastric tissues. Moreover, IL-26 was primarily produced by Th17 and NK cells. IL-26 promoted the proliferation and survival of MKN45 and SGC-7901 gastric cancer cells in a dose-dependent manner. Furthermore, IL-20R2 and IL-10R1, which are two essential receptors for IL-26 signaling, were expressed in both cell lines. IL-26 activated STAT1 and STAT3 signaling; however, the upregulation of the expression of Bcl-2, Bcl-xl and c-myc indicated that the effect of IL-26 is mediated by STAT3 activation. Knockdown of STAT1 and STAT3 expression suggested that the proliferative and anti-apoptotic effects of IL-26 are mediated by the modulation of STAT1/STAT3 activation. In summary, elevated levels of IL-26 in human GC promote proliferation and survival by modulating STAT1/STAT3 signaling.

Tumor-priming converts NK cells to memory-like NK cells

“…Interestingly, gene annotation revealed IL26 to be the gene most upregulated (Table S2) and PDGF-A to be the gene most downregulated (Table S3) in TIML-NK cells as compared with control NK cells. As IL26 mediates both proliferative as well as anti-apoptotic effects 48 and induces T H 1 polarization, 49 it is tempting to speculate that IL26 secreted by TIML-NK cells might modulate subsequent adaptive immune responses. On the other hand, the plateletderived growth factor-A (PDGF-A) has so far not been associated with NK cell function; however, downregulation of the corresponding c-Kit / PDGF receptor on dendritic cells indeed effectively improves NK cell-triggering.…”

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

“…In vitro studies have revealed the role played by Stat3 in cell proliferation, motility and invasiveness [38][39][40]. Similarly, in vivo animal studies have highlighted the fact that Stat3 has an important role to play in gastric tumorigenesis [41][42][43].…”

Interleukin-26: An Emerging Player in Host Defense and Inflammation

“…Even though the current knowledge remains superficial from a wholistic point of view, there is now evidence that the effector function of IL-26 depends upon the type of cellular target and the costimulatory conditions [14,18,21]. Despite the structural similarity with the archetype anti-inflammatory cytokine IL-10, and the sharing of one of its heterodimer receptor subunits, functional studies are compatible with IL-26 driving or sustaining inflammation rather than suppressing it.…”

“…In another study, IL-26 caused decreased proliferation in a colorectal-cancer cell line [11]. In human gastric-cancer cells, on the other hand, IL-26 induces STAT3-dependent upregulation of Bcl-2, Bcl-xl and c-myc malignant carcinoma cells, thereby promoting both cell survival and proliferation [21]. Thus, IL-26 exerts potentially important effects on cancer cells but the current data appear conflicting and it remains for the conceptual importance of IL-26 in cancer to be clarified.…”