Abstract
Hepatic metastasis is the major cause of mortality in colorectal cancer (CRC) patients. Using proteomic analysis, we found sciellin (SCEL) to be specifically expressed in hepatic metastatic CRC cell lines. SCEL knockdown increased CRC cell migration and invasion, while overexpression had the opposite effect. SCEL knockdown also caused cancer cells to form more invasive structures within 3D cultures, increased the mesenchymal marker vimentin, and attenuated the epithelial marker E-cadherin. SCEL increased WNT signaling by activating β-catenin and its downstream target c-myc, and activated mesenchymal-to-epithelial transition (MET) through a SCEL-β-catenin-E-cadherin axis. SCEL showed higher expression in late stage primary CRC than in its hepatic metastatic counterpart. SCEL expression is dynamically modulated by TGF-β1 and hypoxia, revealing a plastic MET mechanism for tumor colonization. Intrahepatic injection in immunodeficient mice revealed that SCEL is necessary for metastatic CRC tumor growth in the liver. These results demonstrate that SCEL is a MET inducer dynamically regulated through the metastasis process. They suggest SCEL may be a useful therapeutic target for preventing or eliminating CRC hepatic metastasis.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer death in the developed world [1]
SCEL is highly expressed in hepatic metastasis colorectal cancer (CRC) cell lines
To identify novel target proteins involved in CRC hepatic metastasis, membrane proteins from four CRC cell lines, SW480, SW620, L1, and L2, were extracted and analyzed using mass spectrometry
Summary
Colorectal cancer (CRC) is the second leading cause of cancer death in the developed world [1]. The liver is the most frequent site of CRC metastasis. During EMT, cancer cells switch off the expression of epithelial markers such as E-cadherin and turn on the expression of mesenchymal markers such as vimentin [6]. EMT is usually linked with stemness properties, including apoptosis resistance, transient quiescence, and self-renewal capacities, revealing cancer stem cell involvement in metastasis [7, 8]. For clonal outgrowth at metastatic sites, the reverse process mesenchymal-to-epithelial transition (MET) is thought to be required for proliferation and differentiation of cancer cells [9]. MET was originally proposed based on the observation that carcinoma metastases usually present a well-differentiated epithelial phenotype [10]. Compared to EMT, very few MET inducers have been identified [14,15,16]
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