Linc1776-UPF1调控乳腺癌化疗耐药和进展转移的机制研究

Breast cancer is a common malignancy in women. Acquisition of drug resistance is one of the main obstacles encountered in breast cancer therapy. To clarify the mechanism of drug resistance is significant for clinical treatment of breast cancer. Long non-coding RNAs (lncRNAs) have been a focus of research in the field of tumor and and the latest studies have revealed that lncRNAs play vital roles in both development and tumorigenesis. However, the relationship between lncRNAs and the development of chemoresistance is not well established. Our previous studies have found that the expression of linc1776 was significantly increased in the Doxorubicin-resistant breast cancer cells, and further that the expression of oup-frameshift 1 (UPF1) protein, as the target of linc1776, was regulated by the lncRNA. The purpose of this project include: 1) Further investigation of the roles of linc1776 and UPF1 in the Doxorubicin-resistance, progression and metastasis of breast cancer cells both in vitro and in vivo, using the stable breast cancer cell lines; 2) Clarification of molecular mechanism underlying the modulation of Doxorubicin-resistance and metastasis of breast cancer cells by linc1776-UPF1; 3) Identification of the detailed molecular mechanism underlying the regulation of UPF1 protein expression by linc1776; 4) Evolution of the the clinical significance of linc1776 and UPF1 expression. Our work will help elucidate the roles of linc1776 and UPF1 in the Doxorubicin-resistance and metastasis of breast cancer, and also help identify novel targets for the diagnosis and treatment for breast cancer.

化疗耐药是导致乳腺癌临床治疗失败的主要原因之一，故阐明耐药机制并寻找新的关键分子靶点，对提高乳腺癌的疗效具有重要意义。基因突变和异常的表观遗传学修饰是化疗耐药的主要机制。近来研究表明长链非编码RNA（lncRNA）在表观遗传学方面发挥重要作用，然而lncRNA在化疗耐药尤其是阿霉素耐药中的作用目前尚不清楚。我们利用lncRNA表达谱芯片发现linc1776在阿霉素耐药细胞中表达明显升高，并通过初步的下游靶基因分析发现linc1776调控上游移码突变蛋白1（UPF1）的表达。本研究拟通过体内体外实验分析linc1776及UPF1在乳腺癌细胞化疗耐药、细胞增殖凋亡及浸润转移中的作用，并进一步明确其分子机制及临床应用价值，同时阐明linc1776调控UPF1蛋白的分子机制。本课题的完成有助于阐明linc1776及UPF1在乳腺癌化疗耐药和进展转移中的作用，也将为乳腺癌的诊治提供新的靶点。

乳腺癌是目前世界范围内最常见的女性恶性肿瘤之一，转移和耐药是导致乳腺癌患者预后不佳乃至死亡的重要原因。深入探讨乳腺癌耐药机制和寻找新的关键分子靶点，对提高乳腺癌治疗的疗效具有重要意义。lncRNA已被证实与多种肿瘤的发生、侵袭转移及耐药有关,有望成为肿瘤诊疗的新靶标。我们利用lncRNA芯片分析阿霉素耐药乳腺癌细胞系231/DOX与其亲本细胞中差异表达的lncRNAs，最终确立了表达明显升高的linc1776作为研究对象。本项目通过干扰及过表达linc1776利用体内、体外实验分析其对乳腺癌增殖，化疗耐药和复发转移的影响。通过生物学综合分析，发现上游移码突变蛋白（Up-frameshitf 1，UPF1）是linc1776的作用蛋白，通过体外实验明确其介导linc1776促耐药转移的潜在机制。然后通过检测临床linc1776和UPF1在乳腺组织中的表达情况明确其临床应用价值。本课题的完成将有助于阐明乳腺癌化疗耐药和进展转移过程中lncRNA所起的作用，也将为三阴性乳腺癌的防治提供新的靶标。