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

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Abstract

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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 31401081) and the Key Science and Technology Program of Shaanxi Province (Grant No. 2019ZDLSF02-05).

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Authors and Affiliations

  1. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Taibai North Road 229, Xi’an, 710069, Shaanxi, China

    Lei Lei, Qing Cao, Guoyan An, Yuejiao Lv, Juan Tang & Jin Yang

  2. Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an, China

    Lei Lei & Jin Yang

Authors
  1. Lei Lei
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  2. Qing Cao
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  3. Guoyan An
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  4. Yuejiao Lv
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  5. Juan Tang
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  6. Jin Yang
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Contributions

Conception and design: LL and JY; acquisition of data: LL, QC, GA, YL and JT; analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): LL and QC; writing and review of the manuscript: LL; study supervision: LL and JY.

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Correspondence to Jin Yang.

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Lei, L., Cao, Q., An, G. et al. DDI2 promotes tumor metastasis and resists antineoplastic drugs-induced apoptosis in colorectal cancer. Apoptosis 28, 458–470 (2023). https://doi.org/10.1007/s10495-022-01796-z

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