Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion

Abstract

Background Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression. Methods Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot. Results In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn’t affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines. Conclusion FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation. Electronic supplementary material The online version of this article (10.1186/s12885-019-5509-4) contains supplementary material, which is available to authorized users.

Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance

“…Many studies have demonstrated its involvement in tumorigenesis and tumor progression: FRG1 mutations occur in patients with thyroid cancer and calcifying fibrous tumor of pleura 36 , 37 . Functionally, FRG1 may act as tumor suppress gene since its expression is reduced in various types of tumor, such as prostate, breast, lung, gastric, etc 38 , 39 . Further, FRG1 knockdown can lead to significantly enhanced invasion and migration abilities of tumor cells 38 .…”

Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer

“…The expression of SP8 was decreased in primary gastric cancer compared with normal gastric mucosa in a recent study (Chang et al, 2009). FRG1 expression was decreased in PCa tissues and that affected the migration and invasion of cancer cells (Tiwari et al, 2019). Deleterious mutations of FRG1, which had been identified in calcified pleura fibrous tumor and follicular thyroid cancer, were suggested to contribute to tumorigenesis (Erinjeri et al, 2018;Mehrad et al, 2018).…”

Role of FRG1 in predicting the overall survivability in cancers using multivariate based optimal model

“…However, recent studies have demonstrated the role of FRG1 in tooth germ development and angiogenesis [6,22]. Our group has revealed its role in tumor development [7]. Being part of the spliceosomal C complex, FRG1's downregulation might lead to instability and disruption in downstream processes affecting the normal mRNA levels.…”

“…FRG1 affected the proliferation, migration, invasion, and angiogenic potential of cancer cell lines and the expression of G-CSF and MMP10 [6]. Reduced FRG1 expression in AR negative prostate cancer cell lines increased invasiveness and cell migratory properties [7].…”