Vimentin (VIM) is considered a prognostic marker in colorectal cancer (CRC). Our aim is to identify genes that fulfil a “X-low implies VIM-high” Boolean relationship and to evaluate their prognostic value and potential mechanism.
Potential biomarkers related to VIM expression were searched using a bioinformatics approach across gene-expression arrays. Based on subgroup analysis of 2 CRC cohorts, the selected gene was tested for its association with patient’s survival outcomes. The regulatory link between the selected gene and VIM was further examined with in vitro models.
PPM1H was identified as the top candidate in our search. Patients with PPM1H-low tumours have a lower 5-year disease-free survival rate than patients with PPM1H-high tumours in 2 independent cohorts. In multivariate Cox analysis, patients with PPM1H-low tumours were independently associated with relapse in both the discovery cohort (hazard ratio [HR], 1.362; 95% confidence interval [CI], 1.015–1.826; P = 0.039) and the validation cohort (HR for DFS, 4.052; 95% CI, 2.634–6.234; P < 0.001). PPM1H knockdown in CRC cells and growth in the corresponding conditional medium increased VIM expression and colon fibroblast proliferation, indicating a transformation of cancer-association fibroblasts (CAFs). Conversely, educated CAFs also facilitated the growth of CRC cells with low PPM1H expression.
Lack of tumour PPM1H expression identifies a patient subgroup with a high relapse risk, and CRC cells with low expression of PPM1H activate CAFs and inversely get promoted by CAFs.
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We would like to acknowledge Association Dr Hanlin Tang, Department of Microbiology, Second Military Medical University, Shanghai for providing bioinformatics assistance. We thank Prof Dr Xiangyang Xue from the Department of Microbiology and Immunology, Wenzhou Medical University, Zhejiang for their technical support. This work was supported by grants from the National Natural Science Foundation of China (81572451 to WC; 81402005 to FC; 81502416 to YY).
X.X, L.Z., and Y.Y. analysed the whole data independently and presented the same results. F.C. and J.S. were responsible for the follow-up of CRC patients; W.C. and Y.P. were responsible for pathological analysis. Z.F., Y.L., and J.S. involved in the pathological diagnosis and recruitment of the patients in the hospital. X.X., L.Z. and W.C. were responsible for statistical analysis. X.X., Y.Y. and F.C. designed and organised the study and wrote the manuscript.
The authors declare no competing interests.
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The ethics committee of Changhai Hospital ruled that no formal ethics approval was required in this particular case. The study was performed in accordance with the Declaration of Helsinki.
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