Journal
ARCHIVES OF PHARMACAL RESEARCH
Volume 45, Issue 7, Pages 460-474Publisher
PHARMACEUTICAL SOC KOREA
DOI: 10.1007/s12272-022-01396-0
Keywords
Rab coupling protein; STAT3; Cancer cell invasion; Slug; MT1-MMP
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Funding
- Basic Science Research Program of the National Research Foundation of Korea (NRF) - Ministry of Education, Science, and Technology [NRF-2017R1E1A1A01074091, 2022R1A2C1004019]
- National Research Foundation of Korea [2022R1A2C1004019] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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This study identifies the important role of STAT3 in RCP-induced cancer cell invasion. The expression levels of RCP and p-STAT3 are closely correlated in ovarian cancer patients, and high expression of both proteins is associated with poorer survival rates. Mechanistically, RCP induces STAT3 phosphorylation in cancer cells, and the beta 1 integrin/EGFR axis is important for this process. Furthermore, STAT3 activates NF-kappa B to promote Slug and MT1-MMP expression, contributing to cancer cell invasion.
Rab coupling protein (RCP) has been known to induce cancer invasion and metastasis, and STAT3 is one of major oncogenic factors. In the present study, we identify the critical role of STAT3 in RCP-induced cancer cell invasion. Immunohistochemical data of ovarian cancer tissues presented that levels of RCP expression are closely correlated with those of phospho-STAT3 (p-STAT3). In addition, ovarian cancer patients with high expression of both RCP and p-STAT3 had significantly lower progress-free and overall survival rates compared to those with low either RCP or p-STAT3 expression. Mechanistically, RCP induced STAT3 phosphorylation in both ovarian and breast cancer cells. Silencing or pharmacological inhibition of STAT3 significantly inhibited RCP-induced cancer cell invasion. In addition, we provide evidence that the beta 1 integrin/EGFR axis is important for RCP-induced STAT3 phosphorylation. Furthermore, STAT3 activated NF-kappa B for Slug expression that in turn upregulated MT1-MMP expression for cancer cell invasion. Collectively, our present data demonstrate that STAT3 is located downstream of the beta 1 integrin/EGFR axis and induces Slug and MT1-MMP expression for cancer cell invasion.
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