Colorectal cancer CRC is the leading cause of cancer

Colorectal cancer (CRC) is the leading cause of cancer deaths in Taiwan and is also a most common cancer in the world (Huang et al., 2012, Jemal et al., 2011). With early detection and treatment in the initial stage, CRC can be recognized as curable in comparison with other malignant tumors (Levin et al., 2011). However, CSC is still a disastrous malignancy with increasing prevalence and poor prognosis, particularly in stage IV metastatic CRC [4]. As a result, exploring effective anti-tumor compounds against CRC remains an urgent need. In addition to hyperproliferation, metastasis is another important capability of cancer Sapitinib australia that causes approximate 90% of all cancer deaths (Mehlen & Puisieux, 2006). Metastasis is regarded as the capability to escape from a primary tumor, invade into circulation, transfer to a distant tissue site, and form a secondary tumor. Most of the human cancers are derived from epithelial cells, which are polarized and tightly connected with each other and basal lamina via different cell adhesion molecules (CAMs). Thus, thrusting epithelial barrier and breaking epithelial integrity is essential for metastasis of tumor cells. In this study, we aimed to investigate the anti-tumoral effects of HPE on colon cancer focusing on the interference of tumor metastatic capability. We hypothesized that HPE could inhibit migratory ability and invasiveness of colon carcinoma cells, and further explored the underlying cellular mechanism by using both in vitro cell model and in vivo animal model.
Materials and methods
Results
Discussion CD44 is a transmembrane protein with multiple isoforms that have been demonstrated involving in tumor growth and metastasis. Abnormally expression of CD44 has been reported to correlate with tumor metastasis in various cancers (Chen et al., 2017, Fang et al., 2017, Reithmeier et al., 2017). Recent studies implicate that the expression of CD44 is upregulated in colon carcinoma and correlates with the poor clinical outcome (Iseki et al., 2017). The central role of CD44 in metastatic progression might be interaction with tyrosine kinase receptors such as c-MET, an oncoprotein highly associated with tumor proliferation, migration, and invasion. Moreover, increased expression of CD44 and activation of c-MET can subsequently lead to FAK phosphorylation and the downstream signaling activation that promotes cell motility (Nam, Oh, Lee, Yoo, & Shin, 2015). Our findings reveal that HPE downregulates CD44 and c-MET expression, subsequently contributing to inhibition of FAK signaling cascades including paxillin, Akt, RhoA, Rac1, Cdc42, consequently suppressing the metastatic ability of DLD-1 cell. Although RhoB has 86% sequence identity with RhoA, the role of these GDP/GDP-binding GTPases in oncogenesis is quite different. RhoA, like other GTPase members such as Ras, Rac1, and Cdc42, has been demonstrated being able to promote tumor progression, migration, and invasion (Zheng et al., 2017). In contrast, RhoB has been reported being able to inhibit tumor proliferation and induce programmed cell death in both in vitro and in vivo model (Chen et al., 2016, Couderc et al., 2008). In addition, decreased the level of RhoB in lung cancer, head and neck cancer, and brain cancer tissue has been regarded as a poor prognostic marker. Accordingly, downregulation of Rho in tumor cell could promote its transformation, invasion, and metastasis that turn it into a more malignant phenotype. Our findings show that HPE can decrease RhoA expression while increasing RhoB expression, inhibit Akt phosphorylation, and decrease GSK-3β level, indicating that HPE may inhibit the malignant tumorigenesis of CRC cells. Previous studies report that Rho B can downregulate the expression of matrix metalloproteases that is essential for degradation of extracellular matrix components and the following migration and invading to nearby tissue and even to distant sites (Liu, Gu, Wang, Ji, & Mu, 2016). Akt signaling cascade promotes the expression of MMP-2 and MMP-9 via inducing the nuclear translocation of NF-κB and the subsequent binding to MMP promoter. Consistently, our results reveal that HPE inhibits Akt phosphorylation and decreases MMP-9 and MMP-2, consequently contributing to the suppression of tumor metastasis.