PDCD4 Deficiency Aggravated Colitis and Colitis-associated Colorectal Cancer Via Promoting IL-6/STAT3 Pathway in Mice

Abstract

Background

Although programmed cell death (PDCD) 4 is generally considered to be a new tumor suppressor, the consequence of Pdcd4 deficiency in tumorigenesis is not well established. The role of PDCD4 in colitis-associated colorectal carcinoma (CRC) remains unknown.

Methods

Experimental colitis and CRC were induced by dextran sodium sulfate and dextran sodium sulfate with azoxymethane, respectively, in wild type and Pdcd4 knockout (Pdcd4^−/−) mice and were evaluated by clinical examination and histopathology. Levels of cytokines were detected by enzyme-linked immunosorbent assay. Changes in signaling pathways were examined by Western blot and immunofluorescent staining. Cell proliferation was determined by BrdU incorporation and Cell Counting Kit-8 staining.

Results

Pdcd4 deficiency not only aggravated the dextran sodium sulfate–induced acute colitis but also promoted the development of colitis-induced CRC. Mechanically, Pdcd4 deficiency accelerated epithelial cell proliferation during tumorigenesis, markedly up-regulated the expression of proinflammatory cytokines, such as interleukin (IL)-6, and enhanced the activation of signal transducer and activator of transcription (STAT3), a IL-6 downstream effector. Using purified cells, we found that Pdcd4 deficiency increased IL-6 expression in vitro and the susceptibility to IL-6/STAT3 pathway-mediated cell proliferation significantly. Furthermore, blockade of IL-6/STAT3 pathway through sgp130Fc reversed the promoting effect of Pdcd4 deficiency on colonic epithelial cell proliferation in vivo.

Conclusion

The Pdcd4 deficiency accelerates colitis and colitis-associated CRC presumably through up-regulating IL-6/STAT3 pathway, suggesting that PDCD4 plays a protective role in inflammation-associated carcinoma and might be a potential target for the treatment of CRC.

PDCD4, colitis, colitis-associated carcinogenesis, STAT3, IL-6