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耐药是乳腺癌治疗的主要障碍之一。不过，癌细胞发生化疗耐药的具体机制尚不明确。 2019年6月27日，英国《自然》旗下《癌基因》在线发表香港中文大学、江南大学无锡医学院、复旦大学附属肿瘤医院、北京大学医学部的研究报告，发现了引起化疗耐药乳腺癌细胞死亡的新靶点。 该研究发现，激素受体阳性HER2阴性乳腺癌细胞MCF-7阿霉素耐药型与亲本株野生型相比，跨膜蛋白9超家族成员4前体TM9SF4表达水平显著较高。通过小发夹核糖核酸shRNA抑制TM9SF4表达，阿霉素耐药型与亲本株野生型相比，可以显著减少细胞生长并且引发细胞死亡。抑制TM9SF4表达还可显著减少吉西他滨耐药型三阴性乳腺癌细胞MDA-MB-231细胞生长并且引发细胞死亡。 机制研究表明，抑制TM9SF4表达，可以增加阿霉素耐药型MCF-7细胞的蛋白质错误折叠，并且提高内质网应激水平，表现为蛋白质聚集体形成和内质网应激标志表达上调，该作用可以被4-苯丁酸逆转。对于阿霉素耐药型人类乳腺癌异种移植肿瘤无胸腺裸鼠模型，抑制TM9SF4表达可以显著减少异种移植肿瘤生长。对于化疗耐药乳腺癌患者，化疗可以增加乳腺肿瘤标本的TM9SF4蛋白表达。 因此，该研究结果表明，TM9SF4蛋白具有减少内质网应激和防止化疗耐药乳腺癌细胞发生凋亡型或坏死型细胞死亡的作用，靶向TM9SF4有望成为克服乳腺癌化疗耐药的新策略。 Oncogene. 2019 Jun 27. [Epub ahead of print] Knockdown of TM9SF4 boosts ER stress to trigger cell death of chemoresistant breast cancer cells. Yifei Zhu, Mingxu Xie, Zhaoyue Meng, Lai-Kwok Leung, Franky Leung Chan, Xin Hu, Kaiwen Chi, Cuiling Liu, Xiaoqiang Yao. Chinese University of Hong Kong, Hong Kong, China; Jiangnan University, Wuxi, China; Fudan University Shanghai Cancer Center, Shanghai, China; Peking University Health Science Center, Beijing, China. Drug resistance is one of the major obstacles to breast cancer therapy. However, the mechanisms of how cancer cells develop chemoresistance are still not fully understood. In the present study, we found that expression of TM9SF4 proteins was much higher in adriamycin (ADM)-resistant breast cancer cells MCF-7/ADM than in its parental line wild-type breast cancer cells MCF-7/WT. shRNA-mediated knockdown of TM9SF4 preferentially reduced cell growth and triggered cell death in chemoresistant MCF-7/ADM cells compared with MCF-7/WT cells. Knockdown of TM9SF4 also reduced cell growth and triggered cell death in chemoresistant MDA-MB-231/GEM cells. Mechanistic studies showed that TM9SF4 knockdown increased protein misfolding and elevated endoplasmic reticulum (ER) stress level in MCF-7/ADM cells, as indicated by aggresome formation and upregulated expression of ER stress markers, the effect of which was reversed by a small molecule chaperone 4-phenybutyric acid. In an athymic nude mouse model of ADM-resistant human breast xenograft tumor, knockdown of TM9SF4 decreased the growth of tumor xenografts. In chemoresistant breast cancer patients, chemotherapy increased the expression of TM9SF4 proteins in breast tumor samples. Taken together, these results uncovered a novel role of TM9SF4 proteins in alleviating ER stress and protecting chemoresistant breast cancer cells from apoptotic/necrotic cell death. These results highlight a possible strategy of targeting TM9SF4 to overcome breast cancer chemoresistance. DOI: 10.1038/s41388-019-0846-y
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