Abstract
BackgroundVimentin (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.MethodsPotential 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.ResultsPPM1H 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.ConclusionsLack 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.
Highlights
Vimentin (VIM) is considered a prognostic marker in colorectal cancer (CRC)
PPM1H identified by bioinformatics analysis The search for genes that fulfil a “X-low implies VIM-high” Boolean relationship revealed 95 genes with a false-discovery rate (FDR) < 0.005
The CRC subtype with enriched mesenchymal components is associated with poor prognosis and chemo-resistance.[5,6,7,8,9,10,11,12,14,15]
Summary
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. CONCLUSIONS: 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. Colorectal cancer (CRC) is one of the most common and lethal malignancies worldwide, accounting for approximately 1 in 10 cancer cases and deaths.[1] Patients with localised and regional CRC generally receive surgical resection.[2] a subset of these patients will relapse or develop metachronous metastases, which often lead to high mortality.[3] Microarray-based gene-expression profiling has identified several prognostic signatures[3,4] and molecular subtypes[5,6,7,8] in CRC, and many of these profiles consistently emphasises that expanded mesenchymal components surrounding tumour cells, especially cancer-associated fibroblasts (CAFs), may importantly contribute to patient prognosis and drug resistance.[9,10,11,12] CAFs are a heterogeneous and plastic population characterised by enhanced secretory phenotypes, robust autocrine activation and dynamic immunomodulatory functions that mainly originate from resident fibroblasts in tumours.[13] The conversion of quiescent fibroblasts to CAFs is accompanied by unregulated molecule markers, such as αSMA, vimentin (VIM) and FAP.[13,14,15] The interaction between CAFs and tumour cells is quite complicated. The process by which tumour cells educate the microenvironment is poorly understood in CRC
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