Increased expression of cathepsin D is required for L1-mediated colon cancer progression
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Sayon Basu1, Sanith Cheriyamundath1, Nancy Gavert1, Thomas Brabletz2, Gal Haase1 and Avri Ben-Ze’ev1
1 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
2 Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuernberg, Erlangen 91054, Germany
|Avri Ben-Ze’ev,||email:||[email protected]|
Keywords: L1; cathepsin D; colon cancer; metastasis; Wnt/
Received: July 08, 2019 Accepted: August 05, 2019 Published: August 27, 2019
Hyperactivation of Wnt/β-catenin target genes is considered a key step in human colorectal cancer (CRC) development. We previously identified the immunoglobulin-like cell adhesion receptor L1 as a target gene of β-catenin/TCF transactivation that is localized at the invasive edge of CRC tissue. Using gene arrays, we discovered a number of downstream target genes and signaling pathways conferred by L1 overexpression during colon cancer progression. Here, we have used a proteomic approach to identify proteins in the secretome of L1-overexpressing CRC cells and studied the role of the increase in the aspartate protease cathepsin D (CTSD) in L1-mediated colon cancer development. We found that in addition to the increase in CTSD in the secretome, the RNA and protein levels of CTSD were also induced by L1 in CRC cells. CTSD overexpression resulted in elevated proliferation under stress and increased motility, tumorigenesis and liver metastasis, although to a lesser extent than after L1-transfection. The suppression of endogenous CTSD in L1-expressing cells blocked the increase in the proliferative, motile, tumorigenic and metastatic ability of CRC cells. Enhancing Wnt/β-catenin signaling by the inhibition of GSK3β resulted in increased endogenous CTSD levels, suggesting the involvement of the Wnt/β-catenin pathway in CTSD expression. In human CRC tissue, CTSD was detected in epithelial cells and in the stromal compartment at the more invasive areas of the tumor, but not in the normal mucosa, indicating that CTSD plays an essential role in CRC progression.
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