Low Expression of SLC7A11 Confers Drug Resistance and Worse Survival in Ovarian Cancer via Inhibition of Cell Autophagy as a Competing Endogenous RNA.
Low Expression of SLC7A11 Confers Drug Resistance and Worse Survival in Ovarian Cancer via Inhibition of Cell Autophagy as a Competing Endogenous RNA.
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SLC7A11 的低表达通过作为竞争性内源 RNA 抑制细胞自噬而赋予卵巢癌耐药性和更差的生存率。
DOI：
10.3389/fonc.2021.744940
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发表时间：
2021
影响因子：
4.7
通讯作者：
Yin F
中科院分区：
文献类型：
--
作者：
Ke Y;Chen X;Su Y;Chen C;Lei S;Xia L;Wei D;Zhang H;Dong C;Liu X;Yin F
耐药性是卵巢癌（OC）化疗失败的主要原因，而识别自噬的潜在药物靶点是克服耐药性的一种新颖且有前景的方法。在这项研究中，从三个自噬相关数据库中鉴定出了 131 个与自噬相关的基因，根据癌症基因组图谱卵巢癌队列，其中 14 个基因在 90 种耐药 OC 组织和 197 种敏感组织中存在差异表达。在这 14 个基因中，与对照组相比，SLC7A11 在两种紫杉醇耐药 OC 细胞（HeyA8-R 和 SKOV3-R）以及 90 个耐药组织中显着降低。体外过表达SLC7A11显着增加HeyA8-R细胞对紫杉醇的敏感性，抑制集落形成，诱导细胞凋亡并阻滞细胞周期。此外，在 1815 名 OC 患者中，低 SLC7A11 表达与较差的总生存期 (OS)、无进展生存期 (PFS) 和进展后生存期 (PPS) 相关。从机制上讲，基于 32 种肿瘤类型的泛癌分析，SLC7A11 作为竞争性内源性 RNA (ceRNA) 强烈调节细胞自噬。具体来说，作为自噬基因STX17、RAB33B和UVRAG的ceRNA，SLC7A11分别在20个、12个和12个不同肿瘤、379个OC组织和90个耐药OC组织中与这三个基因强阳性共表达，并且前两者在SLC7A11过表达的HeyA8-R细胞中显着上调。此外，SLC7A11诱导其他自噬基因的蛋白表达，例如LC3、Atg16L1和Atg7，并且当用紫杉醇处理细胞时，各个蛋白的表达进一步增加。结果强烈表明，在泛癌和耐药 OC 中，SLC7A11 通过 ceRNA 与上述三个基因的相互作用来调节自噬。此外，STX17 和 UVRAG 的低表达也显着预测低 OS、PFS 和 PPS。 SLC7A11 与 STX17 的组合比单独使用任一组合更能预测 OS 和 PFS，而 SLC7A11 与 UVRAG 的组合则能高度预测 OS 和 PPS。上述结果表明，SLC7A11减少导致OC患者产生耐药性并影响低生存率，可能是通过ceRNA与自噬基因的相互作用，因此该基因可以作为OC的治疗靶点和潜在的生物标志物。
Drug resistance is the main cause of chemotherapy failure in ovarian cancer (OC), and identifying potential druggable targets of autophagy is a novel and promising approach to overcoming drug resistance. In this study, 131 genes associated with autophagy were identified from three autophagy-related databases, and of these, 14 were differentially expressed in 90 drug-resistant OC tissues versus 197 sensitive tissues according to the Cancer Genome Atlas ovarian cancer cohort. Among these 14 genes, SLC7A11 was significantly decreased in two paclitaxel-resistant OC cells (HeyA8-R and SKOV3-R) and in 90 drug-resistant tissues compared with their controls. In vitro overexpression of SLC7A11 significantly increased the sensitivity of HeyA8-R cells to paclitaxel, inhibited colony formation, induced apoptosis, and arrested cell cycle. Further, low SLC7A11 expression was correlated with poor overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) in 1815 OC patients. Mechanistically, SLC7A11 strongly regulated cell autophagy as a competing endogenous RNA (ceRNA) based on pan-cancer analyses of 32 tumor types. Specifically, as a ceRNA for autophagy genes STX17, RAB33B, and UVRAG, SLC7A11 was strongly and positively co-expressed with these three genes in 20, 12, and 12 different tumors, respectively, in 379 OC tissues and in 90 drug-resistant OC tissues, and the former two were significantly upregulated in SLC7A11-overexpressed HeyA8-R cells. Further, SLC7A11 induced the protein expression of other autophagy genes, such as LC3, Atg16L1, and Atg7, and the expression of the respective proteins was further increased when the cells were treated with paclitaxel. The results strongly suggest that SLC7A11 regulates autophagy via ceRNA interactions with the three abovementioned genes in pan-cancer and in drug-resistant OC. Moreover, low expression of STX17 and UVRAG also significantly predicted low OS, PFS, and PPS. The combination of SLC7A11 with STX17 was more predictive of OS and PFS than either individually, and the combination of SLC7A11 with UVRAG was highly predictive of OS and PPS. The above results indicated that decreased SLC7A11 resulted in drug resistance and effected low rates of survival in OC patients, probably via ceRNA interactions with autophagy genes, and thus the gene could serve as a therapeutic target and potential biomarker in OC.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
NCALD 通过作为卵巢癌 CX3CL1 的 ceRNA 影响耐药性和预后。
影响因子：
4
作者：
Dong, Caihua;Yin, Fuqiang;Liu, Xia
通讯作者：
Liu, Xia
影响因子：
14.9
作者：
Homma K;Suzuki K;Sugawara H
通讯作者：
Sugawara H
DOI：
10.1126/science.1187197
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cazalla D;Yario T;Steitz JA
通讯作者：
Steitz JA