Lin Xiaoti, Chen Weiyu, Wei Fengqin, Zhou Binhua P, Hung Mien-Chie, Xie Xiaoming
Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Department of Oncology, The Affiliated Xiang'an Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian, 361003, China.
Int J Cancer. 2017 Jun 1;140(11):2517-2525. doi: 10.1002/ijc.30658. Epub 2017 Mar 16.
The identification and understanding of the molecular network of cancer stem cells (CSCs) have had a profound impact on our view of carcinogenesis and treatment strategy. Unfortunately, a major problem is that serial passages of CSCs from clinical solid tumor specimens currently are not available in any lab, and thus, reported data are difficult to confirm and intensively interrogated. Here, we have generated two tumor tissue-derived breast CSC (BCSC) lines that showed prolonged maintenance over 20 serial passages in vitro, while retaining their tumor-initiating biological properties. We then deciphered the intrinsic mechanism using analyses of mRNA expression array profiles. It has been determined that pro-opiomelanocortin (POMC) is closely related with protein phosphorylation mediated by G-protein-coupled estrogen receptor (GPER) in BCSC. Following, knockdown of POMC inhibits properties of mammosphere formation, CD44 CD24 population, CD44 expression, and clonogenicity ability in BCSC. We found that inhibition of POMC attenuates phosphorylation of AKT2 and GSK3β in BCSC. Further in vivo investigations demonstrated that POMC interference regulates proliferation of BCSC-bearing tumors. Combination of the clinical results that POMC positive expression is frequently upregulated in human breast cancer and POMC positivity correlated with a poor prognosis, POMC is a potential therapeutic target for BCSC. In conclusion, we have successfully established two long-term-cultured BCSC from clinical specimens. We further indicated that POMC acts as a potential therapeutic target and prognostic marker for future treatment of BCSC.
对癌症干细胞（CSCs）分子网络的识别和理解，已对我们关于癌症发生和治疗策略的观点产生了深远影响。不幸的是，一个主要问题是目前任何实验室都无法从临床实体瘤标本中连续传代培养CSCs，因此，所报道的数据难以得到证实和深入研究。在此，我们建立了两种源自肿瘤组织的乳腺CSC（BCSC）系，它们在体外连续传代20次以上仍能长期维持，同时保留其肿瘤起始生物学特性。然后，我们通过对mRNA表达阵列谱的分析来解读其内在机制。已确定促阿片黑素皮质素原（POMC）与BCSC中由G蛋白偶联雌激素受体（GPER）介导的蛋白磷酸化密切相关。随后，敲低POMC可抑制BCSC中乳腺球形成、CD44 CD24群体、CD44表达和克隆形成能力等特性。我们发现抑制POMC可减弱BCSC中AKT2和GSK3β的磷酸化。进一步的体内研究表明，POMC干扰可调节携带BCSC肿瘤的增殖。结合POMC在人类乳腺癌中经常上调表达以及POMC阳性与不良预后相关的临床结果，POMC是BCSC的一个潜在治疗靶点。总之，我们成功地从临床标本中建立了两种长期培养的BCSC。我们进一步表明，POMC作为一个潜在的治疗靶点和预后标志物，可用于未来BCSC的治疗。
