Dataset Information

TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway.

ABSTRACT: Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.

SUBMITTER: Gu J

PROVIDER: S-EPMC8012900 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway.

Gu Jianyou J Huang Wenjie W Zhang Junfeng J Wang Xianxing X Tao Tian T Yang Ludi L Zheng Yao Y Liu Songsong S Yang Jiali J Zhu Liwei L Wang Huaizhi H Fan Yingfang Y

Frontiers in oncology 20210318

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated ...[more]

PMID: 33816264

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Project description:The aim of the present study was to investigate transient receptor potential cation channel subfamily M member 2 (TRPM2), a promising therapeutic target and biomarker for pancreatic ductal adenocarcinoma (PDAC) prognosis, in addition to determining its effects regarding tumor progression and invasion. PDAC is a fatal disease with a poor prognosis, and its associated pathogenic molecular mechanisms remain to be determined. In the present study, combined analysis using genomic and transcriptomic data from two PDAC studies was performed to discover a survival‑associated biomarker of PDAC. Survival analysis for genes mutated in ≥10 patients was performed using a Kaplan‑Meier curve and tested for significance using a log‑rank test. Furthermore, gene‑expression correlation analysis was performed to determine the genes with the strongest correlations to TRPM2. In addition, a Cell Counting Kit‑8 assay, a scratch wound‑healing assay and a Transwell assay were performed in the present study to investigate the proliferative, invasive and metastatic ability of PANC‑1 cells in TRPM2‑overexpressing and downregulated groups. The mutated TRPM2 gene had a strong negative correlation with patient survival probability compared with the normal control group (P=1.06x10‑4). Expression of TRPM2 was strongly correlated with expression of probable phospholipid‑transporting ATPase IM, γ‑parvin, tudor domain containing 9, Toll‑like receptor 7 and Scm‑like with four MBT domains protein 2 according to the criterion of a correlation coefficient >0.5. Furthermore, the results of the present study demonstrated that the TRPM2 overexpression in a PDAC cell line (PANC‑1) promoted cell proliferation, invasion and metastatic ability. TRPM2 represents a potential therapeutic target and prognostic marker for patients with PDAC. TRPM2 regulates cell proliferation, invasion and migration; however, the underlying mechanism requires further investigation in future studies.

Project description:BackgroundUbiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown.MethodsFirst, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism.ResultsWe found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model.ConclusionsThese findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC.

Dataset Information

TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway.

Publications

TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway.

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