DDI2 promotes tumor metastasis and resists antineoplastic drugs-induced apoptosis in colorectal cancer.

The normal colorectal mucosa undergoes precancerous lesions that can develop over time into colorectal cancer (CRC). In the stage of precancerous lesions, DNA replication stress may lead to genome instability. We have performed whole-exome sequencing on genomic DNA obtained from three cases of CRC tissues and identified a novel frameshift mutation of DNA damage inducible 1 homolog 2 gene (DDI2, c. 854 del T). To date, there is no direct evidence that DDI2 is involved in the carcinogenesis of CRC. In this study, we demonstrated that DDI2 is upregulated in the early stage of CRC based on clinical samples and public databases. We also found that 5FU, a standard chemotherapeutic agent for CRC treatment, increased DDI2 mRNA levels in a dose-dependent manner. Depression of DDI2 inhibited CRC cell proliferation, migration and invasion both in vitro and in vivo. Transcriptome sequencing revealed that DDI2 was involved in the mitogen-activated protein kinase (MAPK) pathway. Furthermore, DDI2 resists a MAPK kinase (MEK) inhibitor (trametinib) and a PolyADP-ribose polymerase 1 (PARP1) inhibitor (talazoparib) induced apoptosis in CRC cells. Thus, our results indicate that DDI2 may play a vital role in the carcinogenesis of CRC and could serve as a promising therapeutic target for CRC.