title: PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer.
abstract: BACKGROUND
  Programmed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC.
  
  
  RESULTS
  RNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P<0.001), TNM stage (P<0.01), metastatic progression (P<0.01) and PTEN expression (P<0.001). Univariate analysis revealed that patients with high PD-L1 expression had a poor overall survival (P<0.001). However, multivariate analysis did not support PD-L1 as an independent prognostic factor (P = 0.548). Univariate (P<0.001) and multivariate survival (P<0.001) analysis of 310 located CRC patients revealed that high level of PD-L1 expression was associated with increased risks of metastatic progression. Furthermore, the clinical effect of PD-L1 on CRC was not statistically significant in a subset of 39 patients with no PTEN expression (distant metastasis: P = 0.102; TNM stage: P = 0.634, overall survival: P = 0.482).
  
  
  CONCLUSIONS
  PD-L1 can be used to identify CRC patients with high risk of metastasis and poor prognosis. This clinical manifestation may be partly associated with PTEN expression.
authors.affiliation: Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Song
authors.forename: Defeng
authors.initials: D
authors.lastname: Chen
authors.forename: Biyan
authors.initials: B
authors.lastname: Lu
authors.forename: Chenliang
authors.initials: C
authors.lastname: Wang
authors.forename: Junxiao
authors.initials: J
authors.lastname: Zhang
authors.forename: Lanlan
authors.initials: L
authors.lastname: Huang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Christine L
authors.initials: CL
authors.lastname: Timmons
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Bindong
authors.initials: B
authors.lastname: Liu
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: Huanliang
authors.initials: H
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase