Abstract
BackgroundAberrant activation of the Wnt/β-catenin signaling pathway is one of the most frequent abnormalities in human cancer, including colorectal cancer (CRC). Previous studies revealed pivotal functions of WNT family members in colorectal cancer, as well as their prognostic values. Nevertheless, the prognostic role and mechanisms underlying WNT7b in colorectal cancer development remains unclear.MethodsIn this study, WNT7b expression was measured by immunohistochemical staining of 100 cases of surgically resected human colorectal cancerous tissues as well as matched adjacent normal tissues constructed as tissue microarrays. In vitro studies, we attempted to substantiate the WNT7b expressional pattern previously found in immunohistochemistry staining. We used the colorectal cancer cell-line HCT116 and normal colorectal cell-line FHC for immunofluorescence staining and nuclear/cytoplasmic separated western blotting. We measured epithelial–mesenchymal transition (EMT) markers and migration capacity of HCT116 in the context of WNT7b knocked-down using short interfering RNA. Finally, clinical and prognostic values of WNT7b activation levels were examined.ResultsWNT7b was expressed in the nucleus in adjacent normal tissues. In CRC tissues, nuclear expression of WNT7b was similar; however, membrane and cytoplasmic expression was strikingly enhanced. Consistently, in vitro analysis confirmed the same expression pattern of WNT7b. Compared with FHC cells, HCT116 cells displayed higher levels of WNT7b membrane and cytoplasmic enrichment, as well as higher migration capacity with a sensitized EMT process. Either partial knockdown of WNT7b or blockade of the Wnt/β-catenin signaling pathway reversed EMT process and inhibited the migration of HCT116 cells. Finally, elevated secretion levels of WNT7b were significantly associated with lymphatic and remote metastasis and predicted worse prognosis in the CRC cohort.ConclusionIn summary, we demonstrated that the activation of WNT7b autocrine probably contributes to CRC metastasis by triggering EMT process through the Wnt/β-catenin signaling pathway. High levels of WNT7b autocrine secretion predicts poor outcome in patients with CRC. This molecule is a promising candidate for clinical CRC treatments.
Highlights
Aberrant activation of the Wnt/β-catenin signaling pathway is one of the most frequent abnormalities in human cancer, including colorectal cancer (CRC)
In summary, we demonstrated that the activation of WNT7b autocrine probably contributes to Colorectal cancer (CRC) metastasis by triggering Epithelial–mesenchymal transition (EMT) process through the Wnt/β-catenin signaling pathway
immunohistochemistry staining (IHC) labeling of WNT7b expression pattern in CRC and adjacent normal tissues To evaluate the expression of WNT7b in primary CRC, we performed immunohistochemical staining of tissue microarrays (TMAs) slides of both CRC and adjacent normal tissues (Catalog #: AF3460, R&D system, 1:1000 dilution) (Fig. 1)
Summary
Aberrant activation of the Wnt/β-catenin signaling pathway is one of the most frequent abnormalities in human cancer, including colorectal cancer (CRC). The treatment and prevention of CRC remains a global challenge because of the high risk of invasion and metastasis during CRC progression [3]. The identification of critical molecules regulating CRC metastasis is urgently needed to improve treatment. Epithelial–mesenchymal transition (EMT) is a developmental process by which epithelial cells are converted to mesenchymal cells during embryogenesis, tissue remodeling, wound healing, and tumor metastasis [4, 5]. EMT is abnormally regulated by extracellular stimuli derived from the tumor microenvironment, including growth factors and inflammatory cytokines, along with intra-tumoral physical stresses such as hypoxia [6]. EMT programming allows tumor cells to adapt to the constant changes of the tumor microenvironment, in so doing to successfully metastasize
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