Amplification of a calcium channel subunit CACNG4 increases breast cancer metastasis
Amplification of a calcium channel subunit CACNG4 increases breast cancer metastasis
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DOI：
10.1016/j.ebiom.2020.102646
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发表时间：
2020-02-01
期刊：
影响因子：
11.1
通讯作者：
Done, Susan J.
中科院分区：
文献类型：
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作者：
Kanwar, Nisha;Carmine-Simmen, Katia;Done, Susan J.
背景资料：以前，我们发现染色体17q24.1-24.2的扩增与浸润性导管癌的淋巴结转移、肿瘤大小和淋巴管浸润有关。该扩增子中的基因CACNG 4是一种L型电压门控钙通道γ亚基，在预后不良的乳腺癌中升高。钙稳态是通过维持细胞内低钙水平来实现的。改变钙内流流出机制，使肿瘤细胞保持体内平衡，尽管高血清钙水平往往与晚期癌症（高钙血症）和异常的钙signaling.Methods：在体外2-D和3-D测定，和细胞内钙内流测定被用来测量肿瘤发生的活动，改变CANCG 4水平和钙通道阻滞剂。鸡CAM模型和小鼠转移模型证实了这些结果在vivo.Findings：CACNG 4改变细胞运动在体外，诱导恶性转化的三维培养，并增加肺特异性转移在体内。CACNG 4通过关闭通道孔、抑制钙内流、改变涉及关键存活和转移途径基因（AKT 2、HDAC 3、RASA 1和PKC zeta）的钙信号事件发挥作用。我们的研究结果表明，CACNG 4调节肿瘤生长和传播的潜在途径对于开发针对具有异常钙信号传导的肿瘤中这些通道的治疗具有重要意义。(C)2020年，任作家。由爱思唯尔公司出版
Background: Previously, we found that amplification of chromosome 17q24.1-24.2 is associated with lymph node metastasis, tumour size, and lymphovascular invasion in invasive ductal carcinoma. A gene within this amplicon, CACNG4, an L-type voltage-gated calcium channel gamma subunit, is elevated in breast cancers with poor prognosis. Calcium homeostasis is achieved by maintaining low intracellular calcium levels. Altering calcium influx efflux mechanisms allows tumour cells to maintain homeostasis despite high serum calcium levels often associated with advanced cancer (hypercalcemia) and aberrant calcium signaling.Methods: In vitro 2-D and 3-D assays, and intracellular calcium influx assays were utilized to measure tumourigenic activity in response to altered CANCG4 levels and calcium channel blockers. A chick-CAM model and mouse model for metastasis confirmed these results in vivo.Findings: CACNG4 alters cell motility in vitro, induces malignant transformation in 3-dimensional culture, and increases lung-specific metastasis in vivo. CACNG4 functions by closing the channel pore, inhibiting calcium influx, and altering calcium signaling events involving key survival and metastatic pathway genes (AKT2, HDAC3, RASA1 and PKC zeta).Interpretation: CACNG4 may promote homeostasis, thus increasing the survival and metastatic ability of tumour cells in breast cancer. Our findings suggest an underlying pathway for tumour growth and dissemination regulated by CACNG4 that is significant with respect to developing treatments that target these channels in tumours with aberrant calcium signaling. (C) 2020 The Authors. Published by Elsevier B.V.