Roles of CD133 in microvesicle formation and oncoprotein trafficking in colon cancer

What is it about?

KRAS is an oncogenic protein that acts as an EGFR signaling transducer. Approximately 30% to 40% of colorectal cancer patients harbor KRAS mutation. Patients harboring the mutant KRAS are not only resistant to anti-EGFR chemotherapy, but also tend to exhibit more malignant and metastatic than wild-type KRAS colorectal cancer patients. However, the reason is unclear. Given that KRAS is a membrane-anchored small GTPase, KRAS may be carried by microvesicles as a membrane-bound cargo. In the present study, we found following results. EGF induces CD133 expression via NF-κB activation. CD133 promotes microvesicle budding by regulating the activities of the small GTPases. CD133-containing microvesicles are transported to adjacent cells. Oncogenic KRAS carried by CD133-containing microvesicles promotes the cell migration and invasion of adjacent non-tumorigenic cells. Oncogenic KRAS carried by CD133-containing microvesicles contributes to the development of chemoresistance in colon cancer. Our findings suggest that CD133+ microvesicles act as carriers of the KRAS mutant and mediate the development of chemoresistance. Therefore, CD133 can serve as a therapeutic target for controlling tumor growth and metastasis in anti-EGFR drug resistant colon cancer.

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Why is it important?

Our findings showed that EGF induces CD133expression via NF-kBactivation.CD133 acts as a regulator of MV release by regulating the activities of RhoA and Rac1. CD133+ MVs derived from colon cancer cells harbor the mutant oncoprotein KRAS mutant and activate the KRAS signaling pathway in adjacent nontumorigenic cells.CD133+ MVs were demonstrated to restore cell proliferation and motility in wild-type KRAS expressing colon cancer cells treated with anti-EGFR inhibitor. Our findings suggest that CD133+ MVs act as carriers of the KRAS mutant and mediate the development of chemoresistance. Therefore, CD133 can serve as a therapeutic target for controlling tumor growth and metastasis in anti-EGFR drug–resistant colon cancer.