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The HPA/SDC1 axis promotes invasion and metastasis of pancreatic cancer cells by activating EMT via FGF2 upregulation.

ABSTRACT: Pancreatic cancer is characterized by the absence of early specific clinical symptoms, accompanied with rapid metastasis and invasion. It is one of the most prevalent types of cancer and more importantly, one of the most common types of malignant cancer with the highest mortality rate of all cancer types. The heparanase (HPA)/syndecan-1 (SDC1) axis has been reported to promote tumor growth, invasion, metastasis and angiogenesis in a variety of cancer types; however, studies into the role and mechanism of the HPA/SDC1 axis in pancreatic cancer are limited. The present study aimed to investigate the biological function and clinical significance of the HPA/SDC1 axis in pancreatic cancer. The results demonstrated that HPA is elevated in pancreatic cancer tissues and cell lines, and that its high expression was associated with poor prognosis. HPA was revealed to mediate an increase in fibroblast growth factor 2 (FGF2) expression by upregulating the expression of SDC1. Conversely, silencing HPA mediated the suppression of FGF2 expression. Furthermore, upregulated FGF2 was observed to increase the expression of downstream Palladin proteins by activating the PI3K/Akt signaling pathway and also lead to the activation of epithelial-mesenchymal transition (EMT). Subsequently, EMT was found to promote the migration and invasion of pancreatic cancer cells. In summary, the HPA/SDC1 axis was revealed to serve an important role in the regulation of FGF2, and was found to promote the invasion and metastasis of pancreatic cancer cells. These findings indicated that the HPA/SDC1 axis may be used as an effective therapeutic target for pancreatic cancer.

SUBMITTER: Chen X

PROVIDER: S-EPMC6924090 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The HPA/SDC1 axis promotes invasion and metastasis of pancreatic cancer cells by activating EMT via FGF2 upregulation.

Chen Xidong X Zhao Haichao H Chen Changzhou C Li Jian J He Jiefeng J Fu Xifeng X Zhao Haoliang H

Oncology letters 20191119 1

Pancreatic cancer is characterized by the absence of early specific clinical symptoms, accompanied with rapid metastasis and invasion. It is one of the most prevalent types of cancer and more importantly, one of the most common types of malignant cancer with the highest mortality rate of all cancer types. The heparanase (HPA)/syndecan-1 (SDC1) axis has been reported to promote tumor growth, invasion, metastasis and angiogenesis in a variety of cancer types; however, studies into the role and mec ...[more]

PMID: 31897132

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Project description:Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC.

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The HPA/SDC1 axis promotes invasion and metastasis of pancreatic cancer cells by activating EMT via FGF2 upregulation.

Publications

The HPA/SDC1 axis promotes invasion and metastasis of pancreatic cancer cells by activating EMT via FGF2 upregulation.

Similar Datasets

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