Knockdown of UBXN2A Protein Induces Colorectal Cancer Metastasis Through Up-Regulation of the mTORC2 Signaling Pathway

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Despite advances in treatment regimens, patients diagnosed with colorectal cancer (CRC) develop recurrent disease and chemoresistance that leads to an abysmal 5-year survival rate of 12%. While several signaling pathways involved in colorectal cancer (CRC) tumorigenesis have been well described, critical signaling pathway and their regulators in the metastatic form of CRC still remains unclear. The mTORC signaling pathway, particularly mTORC2 pathway, plays an important role in CRC metastasis, including tumor erbenaesis. The aim of this study was to investigate the possible role of a tumor suppressor protein, named UBXN2A, in CRC metastasis through its regulation of mTORC2 pathway and consequently its effect on VEGF (vascular endothelial growth factor), a protein located downstream of mTORC2 signaling pathways. In this study, wild-type (WT) HCT-116 human colon cancer cell line and two HCT-116 CRISPR/Cas9 based cell lines, which are knock down (KD) for UBXN2A protein, were used. It was found that knocking down UBXN2A protein expression decreases ubiquitination of Rictor protein, a critical member of mTORC2 complex. In contrast, induction of UBXN2A in HCT-116 cells increases ubiquitination of Rictor and leads to proteasomal degradation. In addition, our ubiquitination assay revealed that a low level of UBXN2A in CRISPR cell line decreases the ubiquinated level of VEGF protein. VEGF has a main role when CRC cells start metastasizing to the liver. Furthermore, it was found that cell motility and migration were reduced in HCT116 KD UBXN2A cells. The low level of UBXN2A can increase colorectal cancer metastasis through the up-regulation of mTORC2 signaling pathway and stabilization of Rictor and VEGF signaling. It was demonstrated that UBXN2A knockdown elevates cancer cell motility and migration, which are critical elements for the explanation of the formation and progression of tumor metastasis.

First Advisor

Khosrow Rezvani

Research Area

Basic Biomedical Science

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