STAT3 Knockdown Reduces Pancreatic Cancer Cell Invasiveness and Matrix Metalloproteinase-7 Expression in Nude Mice

Abstract

AimsTransducer and activator of transcription-3 (STAT3) plays an important role in tumor cell invasion and metastasis. The aim of the present study was to investigate the effects of STAT3 knockdown in nude mouse xenografts of pancreatic cancer cells and underlying gene expression.MethodsA STAT3 shRNA lentiviral vector was constructed and infected into SW1990 cells. qRT-PCR and western immunoblot were performed to detect gene expression. Nude mouse xenograft assays were used to assess changes in phenotypes of these stable cells in vivo. HE staining was utilized to evaluate tumor cell invasion and immunohistochemistry was performed to analyze gene expression.ResultsSTAT3 shRNA successfully silenced expression of STAT3 mRNA and protein in SW1990 cells compared to control cells. Growth rate of the STAT3-silenced tumor cells in nude mice was significantly reduced compared to in the control vector tumors and parental cells-generated tumors. Tumor invasion into the vessel and muscle were also suppressed in the STAT3-silenced tumors compared to controls. Collagen IV expression was complete and continuous surrounding the tumors of STAT3-silenced SW1990 cells, whereas collagen IV expression was incomplete and discontinuous surrounding the control tumors. Moreover, microvessel density was significantly lower in STAT3-silenced tumors than parental or control tumors of SW1990 cells. In addition, MMP-7 expression was reduced in STAT3-silenced tumors compared to parental SW1990 xenografts and controls. In contrast, expression of IL-1β and IgT7α was not altered.ConclusionThese data clearly demonstrate that STAT3 plays an important role in regulation of tumor growth, invasion, and angiogenesis, which could be act by reducing MMP-7 expression in pancreatic cancer cells.

STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth

“…STAT3 signaling plays an important role, not only in tumorigenesis but also in the development of therapeutic resistance [37-39]. Constitutive activation of STAT3 has been reported in PanCA patients [40].…”

“…Remarkably, silencing STAT3 also resulted in increased intracellular production of ROS under these experimental conditions in Capan-2 cells. Overexpression and activation of STAT3 occurs in many human cancers including pancreatic cancer and leads to tumor cell growth, invasion, and metastasis [36, 37]. ROS is known to activate various transcription factors including STAT3 to regulate wide variety of cellular processes including inflammation, cell transformation, tumor cell survival, proliferation, invasion, angiogenesis, and metastasis [55-57].…”

Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway

“…Aberrant activation of STAT3 in the pancreas accelerates pancreatic intraepithelial neoplasia progression and PDAC development (7), and activated STAT3 signaling prevents cell apoptosis and confers resistance to chemotherapeutic agents in pancreatic carcinogenesis (8). Furthermore, STAT3 knockdown reduces pancreatic cancer cell invasiveness and expression of matrix metalloproteinase-7 in nude mice (9). Inhibition of STAT3 activity by sorafenib also enhances TNF-related apoptosis-inducing ligand-mediated apoptosis in human pancreatic cancer cells (10).…”

SMAD4 and its role in pancreatic cancer

“…When restoring SMAD4 in PC cells, the TGF-β induced NFkappaB activity was even counteracted [41]. STAT3, an important or critical regulator for PC growth, invasion, and angiogenesis that had been proven by our research team [42][43][44], was another activated downstream of TGF-β/ SMAD4-independent signaling [45]. The receptor tyrosine kinase recepteur d'origine nantais (RON), a member of proto-oncogene family, was up-regulated by the cross talk of TGF-β/SMAD4-independent signaling and the RON pathway, whose activation presented invasive phenotype [46].…”