Low tumour PPM1H indicates poor prognosis in colorectal cancer via activation of cancer-associated fibroblasts.

Authors:
Xiaowen Xu
Xiaowen Xu
Changchun Institute of Applied Chemistry
China
Li Zhu
Li Zhu
College of Animal Science and Technology
East Lansing | United States
Yun Yang
Yun Yang
Wenzhou University
China
Zhuo Feng
Zhuo Feng
Northeast Agricultural University
China
Ye Li
Ye Li
School of Marine Sciences
New Bedford | United States
Wenjun Chang
Wenjun Chang
Second Military Medical University
Jinke Sui
Jinke Sui
Shanghai Changhai Hospital

Br J Cancer 2019 May 16;120(10):987-995. Epub 2019 Apr 16.

Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Rd., Shanghai, 200433, China.

Background: 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.

Methods: 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.

Results: 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.

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.

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http://dx.doi.org/10.1038/s41416-019-0450-5DOI Listing
May 2019

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