Abstract
Metastasis is the leading cause of death for colorectal cancer (CRC). However, the protein transport process involved in CRC metastasis remains unclear. In this report, we use whole-exome sequencing and bioinformatics analysis to identify somatic mutations in CRC samples and found mutations of the protein transport gene Sec23 homolog B (SEC23B) in patients with metachronous liver metastasis. We show that deletion of SEC23B suppresses the membrane localization of adhesion proteins and augments cell mobility. SEC23B mutations either cause a premature stop (C649T) or impair its protein transport activity (C1467G and T488C + G791A + G2153A). Furthermore, SEC23B mutations inhibit the transport of epithelial cell adhesion molecule (EPCAM) and CD9 molecule, thereby attenuating cell adhesion and promoting invasiveness both in vitro and in vivo. Taken together, these data demonstrate the important impact of SEC23B mutations on metastasis, and we propose that SEC23B is a potential suppressor of CRC metastasis.
Highlights
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide
To identify mutations associated with CRC metastasis, we chose patients who were at the pathologic Tumor Node Metastasis (TNM) stage II (based on the seventh edition of the American Joint Committee on Cancer (AJCC) TNM staging system28)
These patients had no evidence of synchronous liver metastasis by computed tomography (CT) scan and no pathologic evidence of positive local/regional lymph nodes in the resected CRC specimen
Summary
According to the World Health Organization (WHO), nearly 1.1 million individuals are diagnosed with CRC each year[1]. More than half of CRC patients develop metastatic lesions, and liver is the most frequently involved organ[2,3]. CRC liver metastasis is divided into synchronous liver metastasis found within 6 months of diagnosis, and metachronous liver metastasis (MLM) found later than six months after diagnosis. There have been numerous studies on the mechanisms of CRC synchronous metastasis using whole-exome sequencing[4,5,6,7], the mechanisms underlying MLM seem lacking. Metastasis is a sequential, multi-step pathological process, which requires cooperation of proteins inside and outside of cells[8,9].
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