LINC00589竞争吸附RNA结合蛋白PIWIL2和miR-100-5p并同时调控乳腺癌 HER2 靶向耐药及其诱发的肿瘤干细胞化和多药耐药研究

HER2 targeted drug is an important treatments for HER2 positive breast cancer patients, but its resistance is a critical problem to resolve in clinical practice. Furthermore, we recently found that HER2 targeted therapy induced more malignant phenotypes, cancer stem-like properties and multidrug resistance in breast cancer cell. How to re-sensitize resistant cells to HER2 targeted therapy, reverse the stemness and multidrug resistance simultaneously is urgent to breast cancer. However, the related research areas are still blank. Our recent studies have proved that several RNA-related molecules and proteins play a key role in trastuzumab resistance, cancer stem cell, and multidrug resistance in breast cancer. Here, from a new perspective of long non-coding RNA (lncRNA), microRNA (miRNA), RNA binding proteins and interaction among them, we expect using trastuzumab resistant breast cancer cell, nude tumorigenesis mice models and breast cancer clinical data to confirm the novel mechanism: long noncoding RNA LINC00589 bind competitively with (sponges) RNA binding protein PIWIL2 and miR-100-5p, then regulates trastuzumab resistance, cancer stemness and multidrug resistance simultaneously through modulating MUC4. This study will provide new therapeutic strategies and candidate targets for breast cancer patients.

HER2靶向药物是HER2阳性乳腺癌的重要治疗手段，但耐药却是亟待解决的难题。更为震惊的是，我们近期发现，乳腺癌获得HER2靶向耐药（由HER2靶向药物曲妥珠单抗诱导）的同时，恶性表型增加并且表现出肿瘤干细胞样特征和多药耐药性。如何同时逆转乳腺癌HER2靶向耐药及其诱发的肿瘤干细胞化和多药耐药显得尤为重要，但相关研究领域尚属空白。我们预实验证实，非编码RNA分子和相关蛋白在乳腺癌HER2靶向耐药、干细胞化和多药耐药中发挥关键作用。因此，本课题从lncRNA、miRNA、RNA结合蛋白三者相互作用的全新视角，用HER2靶向耐药乳腺癌细胞、裸鼠荷瘤模型及乳腺癌临床数据，阐释长链非编码RNA LINC00589竞争性“海绵”吸附RNA结合蛋白PIWIL2、miR-100-5p，并通过MUC4同时调控乳腺癌HER2靶向耐药、干细胞化和多药耐药的新机制，为乳腺癌提供新的治疗策略和候选药物靶点。

HER2靶向治疗药物是治疗HER2阳性乳腺癌的靶向药物，HER2靶向耐药及其诱发的乳腺癌干细胞化和多药耐药是HER2阳性乳腺癌治疗亟待解决的关键难题，但是同时调控这些过程的关键联接分子却仍然未知。本课题通过细胞学和裸鼠动物体内实验发现LINC00589同时逆转乳腺癌HER2靶向耐药及其干细胞化及多药耐药。临床数据表明LINC00589可以乳腺癌患者对HER2靶向治疗反应性的标记物分子，并且与HER2阳性乳腺癌治疗预后相关。分子机制上，我们发现LINC00589能够吸miR-100和miR-452，并且调控其下游靶基因DLG5和PRDM16，进而调控关键癌基因MUC4的稳定性。同时，我们还发现，PWIL2能够与LINC00589和MUC4的mRNA分子结合，从而构成长链非编码RNA、miRNA和mRNA共同构成的RNA调控网络。这些研究结果可以为评估HER2靶向治疗反应性及预后提供新的标记分子，为克服其耐药的乳腺癌提供新的治疗策略和候选药物靶点。

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