TRPM7 通过钙相关的 PI3K / AKT 致癌信号促进卵巢癌细胞的上皮-间充质转化。
TRPM7 promotes the epithelial-mesenchymal transition in ovarian cancer through the calcium-related PI3K / AKT oncogenic signaling.
机构信息
Hunan clinicaI research center in gynecologic cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283, Tongzipo Road, Changsha, 410013, Hunan, People's Republic of China.
University of South China, Hengyang, 421001, People's Republic of China.
出版信息
J Exp Clin Cancer Res. 2019 Feb 28;38(1):106. doi: 10.1186/s13046-019-1061-y.
BACKGROUND
The epithelial-mesenchymal transition (EMT) is crucial for metastasis and positively regulated by calcium-related signaling. The melastatin-related transient receptor potential 7 (TRPM7) regulates a non-selective cation channel and promotes cancer metastasis. However, the mechanisms underlying the action of TRPM7 in ovarian cancer are unclear.
METHODS
The expression of TRPM7 and EMT markers (Vimentin, N-cadherin, Twist and E-cadherin) in ovarian cancer samples was detected. TRPM7was knockdown by shRNA in Ovarian cancer cell lines to examine calcium [Ca2+]i, EMT markers and PI3K/AKT markers. Various cellular assays, such as invasion and migration, were performed in vitro, and further confirmed in vivo.
RESULTS
TRPM7 expression is negatively correlated with E-cadherin, but positively with N-cadherin, Vimentin and Twist expression in ovarian cancer samples. TRPM7 depletion inhibited the migration and invasion in SKOV3 and OVCAR3 cells. In addition, TRPM7 silencing decreased the lung metastasis of SKOV3 tumors and prolonged the survival of tumor-bearing mice. Similar to that of TRPM7 silencing, treatment with MK886, a potent 5-lipoxygenase inhibitor to reduce TRPM7 expression, and/or BAPTA-AM, an intracellular calcium chelator, significantly mitigated the Epidermal growth factor (EGF) or Insulin-like growth factors (IGF)-stimulated migration, invasion, and the EMT in ovarian cancer cells by decreasing the levels of intracellular calcium [Ca2+]i. Furthermore, treatment with LY2904002, a PI3K inhibitor, also inhibited the migration, invasion, and treatment with both LY2904002 and BAPTA-AM further enhanced their inhibition in ovarian cancer cells. Moreover, treatment with BAPTA-AM mitigated the IGF-stimulated migration, invasion, particularly in TRPM7-silenced ovarian cancer cells. Finally, TRPM7 silencing attenuated the PI3K/AKT activation, which was enhanced by BAPTA-AM, MK886 or LY2904002 treatment in ovarian cancer cells.
CONCLUSIONS
TRPM7 silencing inhibited the EMT and metastasis of ovarian cancer by attenuating the calcium-related PI3k/AKT activation. Our findings suggest that TRPM7 may be a therapeutic target for intervention of ovarian cancer.
背景
上皮-间质转化（EMT）对于转移至关重要，并受到钙相关信号的正向调节。雷帕霉素靶蛋白 7（TRPM7）调节非选择性阳离子通道并促进癌症转移。然而，TRPM7 在卵巢癌中的作用机制尚不清楚。
方法
检测卵巢癌样本中 TRPM7 和 EMT 标志物（波形蛋白、N-钙黏蛋白、Twist 和 E-钙黏蛋白）的表达。通过 shRNA 在卵巢癌细胞系中敲低 TRPM7，以检查钙[Ca2+]i、EMT 标志物和 PI3K/AKT 标志物。进行了各种细胞测定，例如体外侵袭和迁移，并在体内进一步证实。
结果
TRPM7 的表达与卵巢癌样本中的 E-钙黏蛋白呈负相关，但与 N-钙黏蛋白、波形蛋白和 Twist 呈正相关。TRPM7 耗竭抑制 SKOV3 和 OVCAR3 细胞的迁移和侵袭。此外，TRPM7 沉默减少了 SKOV3 肿瘤的肺转移并延长了荷瘤小鼠的存活时间。与 TRPM7 沉默相似，用强效 5-脂氧合酶抑制剂 MK886 降低 TRPM7 表达和/或细胞内钙螯合剂 BAPTA-AM 处理显著减轻表皮生长因子（EGF）或胰岛素样生长因子（IGF）刺激的迁移、侵袭和卵巢癌细胞中的 EMT，通过降低细胞内钙[Ca2+]i 水平。此外，用 PI3K 抑制剂 LY2904002 处理也抑制了迁移和侵袭，并且在用 LY2904002 和 BAPTA-AM 处理时进一步增强了它们在卵巢癌细胞中的抑制作用。此外，BAPTA-AM 处理减轻了 IGF 刺激的迁移，特别是在 TRPM7 沉默的卵巢癌细胞中。最后，TRPM7 沉默减弱了 PI3K/AKT 的激活，而 BAPTA-AM、MK886 或 LY2904002 处理增强了这种激活。
结论
TRPM7 沉默通过减弱钙相关 PI3k/AKT 激活抑制了卵巢癌的 EMT 和转移。我们的研究结果表明，TRPM7 可能是干预卵巢癌的治疗靶点。
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