Smoking promotes colorectal cancer via the CKAP2L/AREG axis

The link between smoking and colorectal Cancer (CRC) is well‑established; however, further research is needed to fully understand the specific effects of tobacco on the development of this type of Cancer. The aim of the present study was to investigate the relationship between smoking and CRC, as well as to identify key genes involved in smoking‑enhanced CRC progression. To confirm the association between smoking and CRC, analyses of clinical data from the National Health and Nutrition Examination Survey database and genome‑wide association studies data were integrated. In addition, RNA Sequencing (RNA‑seq) was conducted on HCT116 cells treated with cigarette smoke extract to identify genes related to smoking. To evaluate the malignant phenotypes of CRC cells and potential molecular mechanisms by which key genes promote smoking‑enhanced CRC, a series of cell and animal experiments were performed. The positive association between smoking and CRC was confirmed by both the cross‑sectional study and Mendelian randomization analyses. Furthermore, after treatment of CRC cells with cigarette smoke extract, cell proliferation, migration and invasion were enhanced. Subsequently, cytoskeleton‑associated protein 2‑like (CKAP2L) was filtered out by bioinformatics analysis, indicating its involvement in smoking‑enhanced CRC. After suppressing CKAP2L, the results revealed that cell proliferation was inhibited, and the cell cycle was arrested at S and G2/M phases. Moreover, cell migration and invasion were suppressed after suppressing CKAP2L expression. Further RNA‑seq analysis suggested that CKAP2L promotes the expression of Amphiregulin (AREG). Subsequently, the suppression of AREG resulted in a reduction in the CKAP2L‑promoted proliferation and migration of CRC cells. The results of a chromatin immunoprecipitation assay further confirmed that signal transducer and activator of transcription 3 (STAT3) regulated the transcriptional level of AREG by binding to its promoter. In addition, CKAP2L increased the phosphorylation of STAT3, which subsequently activated the AREG/EGFR pathway, leading to the progression of CRC. In conclusion, the present study demonstrated that smoking may promote CRC progression through the CKAP2L/AREG axis.

AREG; CKAP2L; CRC; Mendelian randomization; National Health and Nutrition Examination Survey; smoking.