State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
Breast Cancer Res Treat. 2014 Jan;143(2):287-99. doi: 10.1007/s10549-013-2809-2. Epub 2013 Dec 15.
Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44(+)/CD24(-) and ALDH1(high) cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.
钙结合蛋白 22kDa（Sorcin）可使癌细胞对化疗药物产生耐药性，从而在多药耐药中发挥重要作用。由于耐药性与侵袭性表型之间存在明确的关联，我们想知道 Sorcin 是否也会影响癌细胞的迁移、侵袭和干细胞特性。我们使用 RNA 干扰（发夹的瞬时和稳定表达）和慢病毒表达载体在多种细胞中实验性地调节 Sorcin 的表达。我们证明，在 MDA-MB-231 乳腺癌细胞中敲低 Sorcin 会减少 CD44(+)/CD24(-) 和 ALDH1(high) 肿瘤干细胞 (CSC) 以及乳腺球体形成能力。我们还观察到 Sorcin 通过 E-钙黏蛋白和血管内皮生长因子的表达部分调节上皮-间充质转化和 CSCs。这导致获得上皮样表型，减弱上皮-间充质转化并抑制裸鼠中的转移。在肺腺癌 A549 细胞和肺纤维肉瘤 HT1080 细胞中也可以再现 Sorcin 耗竭表型。此外，在 MCF7 细胞中过表达 Sorcin（其内源 Sorcin 表达水平较低）可增加其体外迁移和侵袭能力。这为开发下调 Sorcin 表达的治疗策略提供了治疗癌症的理论依据。
