Role Of TRXR? In Colorectal Cancer Development And The Underlying Molecular Mechanism

Nuclear receptors,an important protein family in organism,play an extremely important role in the process of the human's life activities.Alterations of their expression and function may lead to the development of various human diseases including cancer.The current study focuses on the role of an N-terminally truncated form of retinoid X receptor(tRXRa)in the development of colorectal cancer and the underlying molecular mechanism.RXR belongs to the nuclear receptor superfamily,and is implicated in regulating many physiological and pathological activities.Our laboratory previously showed that tRXRa is produced in various tumor cells and tumor tissue including colon cancer,and interacts with the p85a regulatory subunit of phosphatidylinositol 3 kinase(PI3K)in response to tumor necrosis factor(TNFa)treatment,leading to activation of the PI3K/AKT pathway and the growth of tumor cells.Abnormal activation of signal transducer and activator of transcription(STAT3),likely through up-regulation of inflammatory cytokine interleukin-6(IL-6),plays a crucial role in the growth of colorectal tumor.However,how IL6 is up-regulated and whether tRXR? plays a role in IL6 upregulation in colorectal tumor remain to be determined.In this project,we found that tRXRa is overproduced in human colon tumor tissues as compared to adjacent normal tissues.We then used tRXR? transgenic mice recently developed in our lab to determine whether overexpression of tRXRa in colon could promote colorectal tumor development.We found that in azoxymethane/dextran sulfate sodium(AOM/DSS)induced colon cancer model,when compared with wild type mice,tRXRa transgenic mice exhibited increased number of colorectal tumor and their size,demonstrating that tRXR? could promote the growth and development of colorectal tumor in animals.Our mechanistic studies revealed that the level of inflammatory cytokine IL6 induced by DSS was much higher in tRXRa transgenic mice than in the wild-type mice.Furthermore,the activation of STAT3 by DSS in colon from tRXRa transgenic mice occurred much earlier and stronger than that from the wild-type mice.Induction of IL6 production and activation of STAT3 observed in tRXRa transgenic mice correlated with the cytoplasmic localization of tRXR? and increased macrophagy infiltration in tumor,suggesting a role of the nongenomic action of tRXRa in the activation of the inflammatory signaling.Together,our results reveal a role of tRXRa in the growth and development of colorectal tumor through its activation of the inflammatory signaling,and provide a molecular basis for developing tRXR?-based therapeutics for treating colorectal tumor.