Department of Pharmacology, College of Medicine, Konyang University, 821 Medical Science Building, 158 Gwanjeodong-ro, Seo-gu, Daejeon, 35365, Republic of Korea.
Department of Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health Science University, Portland, OR, 97201, USA.
Arch Pharm Res. 2022 Jul;45(7):460-474. doi: 10.1007/s12272-022-01396-0. Epub 2022 Jul 9.
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 β1 integrin/EGFR axis is important for RCP-induced STAT3 phosphorylation. Furthermore, STAT3 activated NF-κB 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 β1 integrin/EGFR axis and induces Slug and MT1-MMP expression for cancer cell invasion.
Rab 衔接蛋白 (RCP) 已被证实可诱导癌症侵袭和转移，而 STAT3 是主要的致癌因子之一。在本研究中，我们确定了 STAT3 在 RCP 诱导的癌细胞侵袭中的关键作用。卵巢癌组织的免疫组织化学数据表明，RCP 表达水平与磷酸化 STAT3（p-STAT3）水平密切相关。此外，与 RCP 和 p-STAT3 低表达的卵巢癌患者相比，两者高表达的患者无进展生存期和总生存期明显更低。从机制上讲，RCP 诱导卵巢癌和乳腺癌细胞中 STAT3 的磷酸化。沉默或药理学抑制 STAT3 可显著抑制 RCP 诱导的癌细胞侵袭。此外，我们提供了证据表明，β1 整合素/EGFR 轴对于 RCP 诱导的 STAT3 磷酸化很重要。此外，STAT3 激活 NF-κB 促进 Slug 的表达，进而上调 MT1-MMP 的表达，促进癌细胞侵袭。总之，我们目前的数据表明，STAT3 位于β1 整合素/EGFR 轴的下游，并诱导 Slug 和 MT1-MMP 的表达以促进癌细胞侵袭。
