The Expression of PRL-3 Correlates With Chromosomal Instability in Colon Cancer and Thyroid Cancer

Abstract

Background: Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We have reported that PRL-3 recruits to telomeric DNA by RAP1/TRF2 protein. Overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomere, telomere deprotection, DNA damage response, chromosomal instability. Aim: To substantiate the previous results and further assess the physiologic relevance of PRL-3 in tumorigenesis, also to explore the prediction role PRL-3 in clinical patients. We detected the expression of PRL-3, telomere length, H3K9me and p-H2AX in the colon cancer and thyroid cancer samples. Methods: We collected 273 colorectal cancer patients and stained with PRL-3 antibody and counterstained with HE. Semiquantitative scoring was performed. Microscopic analysis was done by 2 of the authors. Tissues-chips were obtained from Alenabio (Th802a, thyroid). Results: We retrospectively analyzed a cohort of colorectal cancer tissues (n = 269) stained with anti-PRL-3 (clone 3B6). Although the majority of mitotic cells were bipolar, more multipolar mitoses, an indicator of chromosomal missegregation and chromosomal instability, was observed in PRL-3 positive tissues than in negative tissues (Fig 1A). Also in the PRL-3 positive tissues, more anaphase bridges were detected ( Fig 1A ). These results suggest that PRL-3 levels positively correlate with chromosomal instability in colon cancer tissues. Next, we analyzed 12 freshly dissected colon cancer tissues, with WI38 control and PRL-3-overexpressing cells as reference samples. We detected varying levels of PRL-3 proteins in these tissues, and the level of stably overexpressed PRL-3 in WI38 cells was comparable to some of these tissues. An inverse correlation between PRL-3 and telomere length was revealed, while PRL-3 showed positive correlations with gamma-H2AX and H3K9me3 ( Fig 1B ). We also performed quantitative FISH (qFISH) analysis of telomere length and immunohistochemical staining of PRL-3 with thyroid tissue chips containing 80 samples. We found decreased telomere staining in adenocarcinoma tissues (n = 40) with positive PRL-3 expression, particularly in those of stage I (n = 23) ( Fig 1C ). No correlation was observed in thyroid adenoma (n = 40) or stage II/III/IV adenocarcinoma (n = 17) ( Fig 1C ). With the same thyroid tissue-chip, we evaluated association between PRL-3 and senescence. In stage I thyroid adenocarcinoma tissues, positive staining of PRL-3 correlated with positive H3K9me3 staining, but such correlation was not observed in thyroid adenoma or Stage II/III/IV adenocarcinoma ( Fig 1D ). Conclusion: These results raise the possibility that PRL-3-promoted telomere deprotection and senescence are early events during the development and progression of cancer. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.[Figure: see text]