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BACKGROUND To illustrate the role of DERL3 in regulating the development of Colorectal cancer (CRC) and the underlying molecular mechanisms. METHODS Relative levels of DERL3 in CRC tissues and adjacent normal ones were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between DERL3 level and clinical indicators in CRC patients was analyzed by Chi-square test. After intervening DERL3 level in HT29 and HCT-8 cells, phenotype changes were assessed by cell counting kit-8 (CCK-8) and Transwell assay. The interaction between DERL3 and its downstream target MYCN, and their involvement in the malignant development of CRC were explored. The influence of DERL3 on in vivo growth of CRC was determined by establishing xenograft model in nude mice bearing CRC. RESULTS DERL3 was lowly expressed in CRC tissues than adjacent normal ones. Compared with CRC patients expressing a high level of DERL3, those with a low level presented high rate of lymphatic metastasis or distant metastasis. Overexpression of DERL3 in HT29 cells suppressed proliferative, migratory and invasive capacities, and knockdown of DERL3 in HCT-8 cells yielded the opposite results. MYCN was the downstream target binding DERL3, which was upregulated in CRC tissues and cell lines. MYCN was capable of reversing the regulatory effects of DERL3 on proliferative, migratory and invasive capacities in CRC cells. In vivo overexpression of DERL3 in nude mice bearing CRC inhibited tumor growth by reducing the average tumor volume and tumor weight of CRC tissues. CONCLUSIONS DERL3 is downregulated in CRC samples. Its level is closely linked to lymphatic metastasis or distant metastasis rate in CRC patients. Through negatively regulating MYCN level, DERL3 suppresses proliferative, migratory and invasive capacities in CRC.