Abstract
Low density lipoprotein (LDL) receptor-related protein-6 (LRP6) is an important co-receptor of Wnt pathway, which plays a predominant role in development and progression of colorectal cancer. Recently, dysregulation of LRP6 has proved to be involved in the progression of cancers, but its biological role and clinical significance in colorectal cancer remain unclear. In present study, we revealed that phosphorylation of LRP6 was aberrantly upregulated in colorectal carcinoma correlating with TNM or Dukes staging and worse prognosis. In addition, phosphorylated LRP6 was positively correlated with nuclear accumulation of β-catenin. Overexpression or activation of LRP6 could activate Wnt signaling and promote tumor cell migration in vitro. The activation of LRP6 could induce microtubule dynamics and actin remodeling, probably through regulation of microtubule-associated protein 1B (MAP1B), microtubule actin cross-linking factor 1 (MACF1) and Rho GTPase--RhoA and Rac1. The investigation suggests that LRP6 may be a potential prognostic marker and therapeutic target in the progression of colorectal cancers.
Highlights
Colorectal cancer is the third most common cancer and fourth leading cause of cancer-related deaths worldwide [1, 2] and there is potential for distant metastasis following surgical excision of the primary lesion [3]
To further demonstrate how LRP6 modulates the dynamic process of MT assembly, we evaluated the status of phosphorylation of microtubule-associated protein 1B (MAP1B) (p-MAP1B) and GSK3β in Lovo and HCT116 cells
The vast of evidences have been accumulated that Wnt signaling is involved in progression of colorectal cancers, through either inducing epithelial–mesenchymal transition (EMT) [8], inhibiting tumor cell apoptosis [34] or increasing tumor angiogenesis [35]
Summary
Colorectal cancer is the third most common cancer and fourth leading cause of cancer-related deaths worldwide [1, 2] and there is potential for distant metastasis following surgical excision of the primary lesion [3]. Despite the introduction of new treatments, the 5-year survival rate for metastatic colorectal cancer remains below 10% [4]. The underlying mechanism of metastasis, predictive biomarkers and therapeutic targets for colorectal cancer are under extensive exploration. Loss of function mutation in APC (adenomatous polyposis coli) tumor suppressor gene has been detected in about 85% of sporadic colorectal cancers, which leads to activation of Wnt signaling pathway [5]. Activation of Wnt signaling has been clarified to be involved in initiation and progression of colorectal cancers in past decades. Wnt signaling could be further enhanced by its secreted ligands even in APCmutated situation, suggesting that that hyperactivation of Wnt pathway may be contributed by other alterations in colorectal cancers [8,9,10,11]
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