Overexpression of caudal-related homeobox transcription factor 2 inhibits the growth of transplanted colorectal tumors in nude mice

Abstract

Caudal-related homeobox transcription factor 2 (CDX2) is a transcription factor, which is specifically expressed in the adult intestine. It is essential for the development and homeostasis of the intestinal epithelium and its functions as a tumor suppressor have been demonstrated in the adult colon. The present study aimed to examine the inhibitory effects of the overexpression of CDX2 on subcutaneously-transplanted tumors, derived from LoVo colon cancer cells, in nude mice, and to provide experimental evidence for the biotherapy of colon cancer. A pEGFP-C1-CDX2 eukaryotic expression vector was transfected into the LoVo cells via lipofection, and LoVo cells stably-expressing CDX2 (pEGFP-C1-CDX2 cells) were obtained using G418 selection. A nude mouse subcutaneously-transplanted tumor model was established by inoculating the nude mice with the pEGFP-C1-CDX2 cells, and the effects of overexpression of CDX2 on transplanted tumor growth in the LoVo cells were observed. Western blotting results demonstrated that the protein expression of CDX2 in the LoVo cells was higher in the pEGFP-C1-CDX2 cell group, compared with that in the pEGFP-C1 cell group and the untreated cell group. At 20 days post-inoculation with either pEGFP-C1-CDX2 or pEGFP-C1, the transplanted tumor masses were significantly lower in the pEGFP-C1-CDX2 group, compared with those in the pEGFP-C1 and untreated groups. Immunohistochemistry revealed that the expression levels of CDX2 and matrix metalloproteinase-2 (MMP-2) were detected in each group, and the protein expression of CDX2 was increased in the tumor tissues from the nude mice in the pEGFP-C1-CDX2 group. However the expression of MMP-2 was downregulated in the tumor tissues of the nude mice in the pEGFP-C1-CDX2 group. Taken together, these data suggested that pEGFP-C1-CDX2 cells exhibited suppressed tumor growth in vivo. Overexpression of CDX2 was observed in transplanted tumors in the pEGFP-C1-CDX2 group, and the gene expression of MMP-2 was reduced. These results indicate that CDX2 inhibited the growth of colorectal tumor cells, possibly by downregulating the gene expression.

Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo

“…Histopathological studies have further established that CDX2 expression is reduced in invasive colorectal cancer cells, but is restored in metastases ( 32 , 33 ). Our previous study confirmed that upregulation of CDX2 expression in human colon cancer cells inhibits invasion and migration in vitro and tumorigenicity in vivo ( 13 , 34 ). Therefore, we chose to investigate further CDX2 as a potential agent for anticancer gene therapy.…”

CDX2 inhibits the proliferation and tumor formation of colon cancer cells by suppressing Wnt/β-catenin signaling via transactivation of GSK-3β and Axin2 expression

“…In lung cancer cells, restored CDX2 expression suppressed cell proliferation by arresting the cell G1/S transition 24 . Our previous study revealed that in colon cancer cells, overexpression of CDX2 significantly inhibited cell viability and xenograft tumor formation 30,31 . However, Zhu et al reported that CDX2 promoted HCC cell proliferation by directly transactivating the oncogene CDH-17 45 .…”

“…In human CRC, a CDX2 reduction is inversely related to tumor grade, lymph node metastasis, tumor stage, and a poor prognosis 27,28 . Our previous study indicated that restoration of CDX2 expression markedly suppressed the aggressive phenotype of colon cancer cells, including viability, colony formation, and invasive and migratory abilities 29–31 . Furthermore, CDX2 +/− mice were susceptible to developing colon tumor 32 .…”

Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients

“…The caudal type homeobox 2 transcription factor (CDX2) is a master regulator of intestine-specific genes crucial for the balance between intestinal cell differentiation and proliferation [ 13 , 14 ] and with a fundamental role in the maintenance of intestinal homeostasis [ 15 ]. CDX2 is highly expressed in normal colorectal epithelium, but its levels decrease in a subset of CRCs [ 15 ].…”