Chen Yuan-Yuan, Li Zhi-Zhen, Ye Yuan-Yuan, Xu Feng, Niu Rui-Jie, Zhang Hong-Chen, Zhang Yi-Jian, Liu Ying-Bin, Han Bao-San
Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kong Jiang Road, 200092, Shanghai, China.
Institute of Biliary Tract Disease, Shanghai Jiao Tong University, School of Medicine, 200092, Shanghai, China.
BMC Mol Biol. 2016 Mar 2;17:6. doi: 10.1186/s12867-016-0055-y.
Breast cancer is the most frequent malignancy in women and drug resistance is the major obstacle for its successful chemotherapy. In the present study, we analyzed the involvement of an oncofetal gene, sal-like 4 (SALL4), in the tumor proliferation and drug resistance of human breast cancer.
Our study showed that SALL4 was up-regulated in the drug resistant breast cancer cell line, MCF-7/ADR, compared to the other five cell lines. We established the lentiviral system expressing short hairpin RNA to knockdown SALL4 in MCF-7/ADR cells. Down-regulation of SALL4 inhibited the proliferation of MCF-7/ADR cells and induced the G1 phase arrest in cell cycle, accompanied by an obvious reduction of the expression of cyclinD1 and CDK4. Besides, down-regulating SALL4 can re-sensitize MCF-7/ADR to doxorubicin hydrochloride (ADMh) and had potent synergy with ADMh in MCF-7/ADR cells. Depletion of SALL4 led to a decrease in IC50 for ADMh and an inhibitory effect on the ability to form colonies in MCF-7/ADR cells. With SALL4 knockdown, ADMh accumulation rate of MCF-7/ADR cells was increased, while the expression of BCRP and c-myc was significantly decreased. Furthermore, silencing SALL4 also suppressed the growth of the xenograft tumors and reversed their resistance to ADMh in vivo.
SALL4 knockdown inhibits the growth of the drug resistant breast cancer due to cell cycle arrest and reverses tumor chemo-resistance through down-regulating the membrane transporter, BCPR. Thus, SALL4 has potential as a novel target for the treatment of breast cancer.
乳腺癌是女性中最常见的恶性肿瘤，耐药性是其化疗成功的主要障碍。在本研究中，我们分析了一种癌胚基因，即无翅型MMTV整合位点家族成员4（SALL4），在人乳腺癌肿瘤增殖和耐药性中的作用。
我们的研究表明，与其他五种细胞系相比，耐药乳腺癌细胞系MCF-7/ADR中SALL4表达上调。我们建立了表达短发夹RNA的慢病毒系统，以敲低MCF-7/ADR细胞中的SALL4。SALL4的下调抑制了MCF-7/ADR细胞的增殖，并诱导细胞周期停滞于G1期，同时细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（CDK4）的表达明显降低。此外，下调SALL4可使MCF-7/ADR对盐酸阿霉素（ADMh）重新敏感，并在MCF-7/ADR细胞中与ADMh具有强大的协同作用。SALL4的缺失导致MCF-7/ADR细胞对ADMh的半数抑制浓度（IC50）降低，并对其形成集落的能力产生抑制作用。随着SALL4的敲低，MCF-7/ADR细胞中ADMh的蓄积率增加，而乳腺癌耐药蛋白（BCRP）和原癌基因c-myc的表达明显降低。此外，沉默SALL4在体内也抑制了异种移植肿瘤的生长，并逆转了它们对ADMh的耐药性。
SALL4的敲低通过细胞周期停滞抑制耐药乳腺癌的生长，并通过下调膜转运蛋白BCPR逆转肿瘤化疗耐药性。因此，SALL4有潜力成为治疗乳腺癌的新靶点。
