SUSD2 promotes cancer metastasis and confers cisplatin resistance in high grade serous ovarian cancer
SUSD2 promotes cancer metastasis and confers cisplatin resistance in high grade serous ovarian cancer
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SUSD2促进高级别浆液性卵巢癌的癌症转移并赋予顺铂耐药性
DOI：
10.1016/j.yexcr.2017.12.029
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发表时间：
2018
影响因子：
3.7
通讯作者：
Kong Beihua
中科院分区：
文献类型：
--
作者：
Xu Ying;Miao Chunying;Jin Chengjuan;Qiu Chunping;Li Yinuo;Sun Xiaomei;Gao Min;Lu Nan;Kong Beihua
Notch 3的激活与卵巢癌的潜在进展、肿瘤侵袭、转移和化疗耐药相关，这是高级别浆液性卵巢癌（HGSOC）预后不良的原因。然而，Notch 3的潜在机制还不是很清楚。我们的研究表明SUSD 2是Notch 3的调控基因之一，并且SUSD 2在HGSOC中的蛋白表达升高。我们还发现其高表达水平与较差的总生存率、早期复发和淋巴结转移显著相关。此外，SUSD 2在卵巢癌细胞中的过表达促进上皮间质转化（EMT）和恶性细胞的转移能力。相反，在侵袭性卵巢癌细胞中沉默SUSD 2在体外和体内都抑制了这些过程。在机制上，我们发现SUSD 2通过调节EpCAM的表达促进EMT，而EpCAM沉默逆转了SUSD 2诱导的E-cadherin减少和细胞迁移。进一步的实验表明，SUSD 2在卵巢癌顺铂耐药中的作用可能是通过增强体外自噬。总的来说，这些发现为Notch 3下游基因SUSD 2的作用提供了新的见解，并为HGSOC提供了新的治疗靶点。
The activation of Notch3 is associated with potential progression of ovarian cancer, tumor invasion, metastasis and chemoresistance, which account for poor prognosis of high grade serous ovarian cancer (HGSOC). However, the underlying mechanisms of Notch3 are not yet very clear. Here we show that SUSD2 is one of Notch3-regulating genes and the elevated protein expression of SUSD2 in HGSOC. We also found that its high expression level was significantly correlated with worse overall survival, early recurrence and lymph nodes metastasis. Moreover, overexpression of SUSD2 in ovarian cancer cells promoted epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing SUSD2 in aggressive ovarian cancer cells inhibited these processes both in vitro and in vivo. Mechanistically, we found SUSD2 promoted EMT through regulating the expression of EpCAM and EpCAM silencing reversed SUSD2-induced E-cadherin reduction and cells migration. Further experiments indicated a role of SUSD2 in conferring cisplatin resistance in ovarian cancer probably through enhancing autophagy in vitro. Collectively, these findings shed a new insight into the role of Notch3 downstream gene SUSD2 and provided a new therapeutic target for HGSOC.