功能未知的lncRNA ：TRPC5OS调控乳腺癌耐药的作用与机制研究

Breast chemotherapy resistance is the most important cause which leads to treatment failure in breast cancer. LncRNA TRPC5OS is significantly down-regulated in the chemo-resistant breast cancer tissues via high-through microarray detection. The research reveals that overexpression of TRPC5OS in resistant cell lines could increase cells sensitive to drug significantly. Bioinformatic analysis and experiment data indicated that TRPC5 might be a candidate target gene of TRPC5OS. Overexpression of TRPC5OS could down-regulated TRPC5 dominantly. Literature reported that TRPC5 gene was closely related with drug resistance in breast cancer. Based on these data, we supposed that TRPC5OS could regulate breast cancer chemoresistance through TRPC5. This study intends to clarify TRPC5OS biological characteristics and the specific role of drug resistance in breast cancer. And we will further investigate biological characteristics and regulatory mechanism of TRPC5OS in breast cancer and evaluation TRPC5OS effects on breast cancer drug resistance in vivo. Up to now, there is no report about TRPC5OS in chemoresistance of breast cancer. This study may provide new therapeutic target reversing the drug resistance of breast cancer.

化疗耐药是导致乳腺癌治疗失败的主要原因。TRPC5OS是我们通过芯片技术筛选获得的、显著差异低表达于乳腺癌化疗耐药组织中、功能未知的lncRNA。前期发现，TRPC5OS过表达导致乳腺癌耐药细胞株对化疗药物敏感性增强；生物信息学及预实验结果提示TRPC5可能是TRPC5OS调控的下游靶基因；TRPC5OS过表达可显著抑制TRPC5表达，且TRPC5高表达于乳腺癌耐药组织。因此，我们提出“TRPC5OS可能通过调控TRPC5影响乳腺癌细胞耐药性”的科学假说。本研究拟：阐明TRPC5OS的生物学特征；采用过表达/沉默及挽救策略，在细胞和动物水平系统论证TRPC5OS通过TRPC5影响乳腺癌耐药的机制。鉴于TRPC5OS在乳腺癌耐药中的作用与机制未见报道，本研究将有助于阐明TRPC5OS的生物学功能，并有可能为防治乳腺癌化疗耐药提供新的线索和潜在的新靶标。

背景：乳腺癌是女性最常见的恶性肿瘤,约占女性全身恶性肿瘤的 30%，严重威胁女性的生活质量和生命健康。化疗是乳腺癌的主要治疗手段之一。然而,乳腺癌细胞对结构和功能均不同的化疗药物会产生多药耐药现象，影响肿瘤化疗效果,成为乳腺癌临床治疗失败的主要原因。 LncRNA TRPC5OS是申请者通过芯片技术筛选到的、差异低表达于化疗耐药乳腺癌组织中的一条lncRNA 。.研究内容：探讨lncRNA TRPC5OS在乳腺癌新辅助化疗敏感/耐药组织中的表达规律，以TRPC5为机制主线, 在体水平评价 TRPC5OS 在乳腺癌化疗耐药性转变中的功能与相关分子机制,研究TRPC5OS调控TRPC5表达的分子机制，论证TRPC5OS通过TRPC5影响乳腺癌耐药的机制。.重要结果和关键数据：TRPC5OS在乳腺癌组织中高表达，在癌旁组织中低表达，其在肺癌、结直肠癌、胃癌和乳腺癌等细胞中均有不同程度的表达增加；TRPC5OS能够促进乳腺癌细胞增殖，促进乳腺癌细胞由S期向G2期转变；TRPC5OS与ENO1结合影响糖酵解途径从而调控乳腺癌细胞的葡萄糖摄取。.科学意义：完善临床对乳腺癌耐药过程的理解,为遏制乳腺癌耐药的发生提供新的思路。