MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer.
MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer.
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DOI：
10.3390/cancers13235979
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发表时间：
2021-11-28
期刊：
影响因子：
5.2
通讯作者：
Hughes TA
中科院分区：
文献类型：
--
作者：
Baxter DE;Allinson LM;Al Amri WS;Poulter JA;Pramanik A;Thorne JL;Verghese ET;Hughes TA
癌细胞对细胞毒性化疗的耐药性限制了乳腺癌的治愈率，更好地了解耐药机制将有助于设计改善治疗的策略。我们通过比较化疗前后的匹配乳腺癌样本，以及通过操纵它们在培养的乳腺癌细胞中的水平和测量化疗诱导的细胞死亡，确定了引起化疗耐药性的分子。我们发现microRNA-195和microRNA-26 b通过降低蛋白SEMA 6D的水平诱导乳腺癌对化疗的抵抗。因此，乳腺癌中SEMA 6D的水平可预测化疗后患者的存活率。SEMA 6D是一种预测性标志物，SEMA 6D信号转导为使细胞对化疗敏感提供了治疗机会。背景：预后不良的原发性乳腺癌通常采用细胞毒化疗。然而，即使在这种积极的治疗后，复发仍然相对常见。比较化疗前后匹配的肿瘤可以识别治疗抗性的分子特征，从而可能有助于发现新的预测标记物或化疗增敏靶点。通过这种比较，我们的目的是确定与化疗耐药性相关的microRNA，定义microRNA靶基因，并评估靶点作为化疗反应的预测因子。研究方法：从化疗前和化疗后的匹配乳腺癌组织中激光显微切割癌细胞，所述乳腺癌组织来自对表阿霉素/环磷酰胺化疗显示部分应答的雌激素受体阳性/HER 2阴性乳腺癌（n = 5）。使用qPCR阵列分析MicroRNA表达。用模拟物、抑制剂或siRNA在雌激素受体阳性/HER 2阴性乳腺癌细胞系（MCF 7和MDA-MB-175细胞）中操纵MicroRNA/mRNA表达，并使用MTT和集落形成存活测定来评估化学反应。通过对微小RNA模拟下拉进行RNA测序并将其与含有预测微小RNA结合位点的mRNA进行比较来识别微小RNA靶点。使用METABRIC表达数据集（n = 1979）检验生存相关性。结果如下：miR-195和miR-26 b在治疗后持续上调，其在细胞系中表达的变化导致化疗敏感性的显著差异，与上调驱动耐药性一致。SEMA 6D被定义并确认为microRNA的靶标。SEMA 6D表达减少与化疗耐药性显著相关，这与SEMA 6D是microRNA的下游效应子一致。最后，SEMA 6D在乳腺癌中的低表达与化疗后的生存率低显著相关，但与其他治疗无关。结论：microRNA及其靶点影响化疗反应，允许将SEMA 6D鉴定为化疗反应的预测标志物，可用于指导治疗或作为化疗增敏策略中的靶点。
The resistance of cancer cells to cytotoxic chemotherapy limits cure rates in breast cancer, and a better understanding of resistance mechanisms will aid design of strategies to improve treatments. We have identified molecules that cause chemoresistance through comparison of matched breast cancer samples from before and after chemotherapy treatment, and by manipulating their levels in cultured breast cancer cells and measuring chemotherapy-induced cell death. We show that microRNA-195 and microRNA-26b induce resistance to chemotherapy in breast cancer by reducing the levels of the protein SEMA6D. Accordingly, levels of SEMA6D in breast cancers predict the survival of patients after chemotherapy. SEMA6D is a predictive marker and SEMA6D signaling presents a therapeutic opportunity for sensitizing cells to chemotherapy. Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.
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DOI：
10.1158/1078-0432.ccr-11-2762
发表时间：
2012-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gonzalez-Angulo AM;Iwamoto T;Liu S;Chen H;Do KA;Hortobagyi GN;Mills GB;Meric-Bernstam F;Symmans WF;Pusztai L
通讯作者：
Pusztai L
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：
3.2
作者：
Dong, Lin;Qu, Fangfei
通讯作者：
Qu, Fangfei
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
64.5
作者：
Kim C;Gao R;Sei E;Brandt R;Hartman J;Hatschek T;Crosetto N;Foukakis T;Navin NE
通讯作者：
Navin NE