HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features.
HERV-K activation is strictly required to sustain CD133+ melanoma cells with stemness features.
复制标题
严格需要使用HERV-K激活来维持具有干性特征的CD133+黑色素瘤细胞。
DOI：
10.1186/s13046-016-0485-x
复制
发表时间：
2017-01-26
期刊：
影响因子：
--
通讯作者：
Matteucci C
中科院分区：
文献类型：
--
作者：
Argaw-Denboba A;Balestrieri E;Serafino A;Cipriani C;Bucci I;Sorrentino R;Sciamanna I;Gambacurta A;Sinibaldi-Vallebona P;Matteucci C
黑色素瘤是一种异质性肿瘤，表型转换和CD133标志物与转移促进和化疗耐药有关。CD133阳性（CD133+）亚群也被认为是黑色素瘤肿瘤的推定癌症干细胞（CSC）。人类内源性逆转录病毒K型（HERV-K）已被描述为在黑色素瘤进展过程中异常激活，并与疾病的发病机制有关。先前，我们报道了应激诱导的HERV-K活化促进细胞恶性转化并降低黑色素瘤细胞的免疫原性。在此，我们研究了微环境修饰过程中HERV-K与CD133+黑色素瘤细胞之间的相关性。我们实验室从原发人类黑色素瘤病变中分离出的TVM-A12细胞系和其他商业黑色素瘤细胞系（G-361、WM-115、WM-266-4和A375）在标准细胞和干细胞培养基中培养和维持。通过RNA干扰、Real-time PCR、流式细胞术分析、自我更新和迁移/侵袭实验来表征细胞行为和HERV-K表达。暴露于干细胞培养基的黑色素瘤细胞经历表型转换和CD133+黑色素瘤细胞的扩增，同时由HERV-K激活促进。值得注意的是，与亲本细胞系相比，CD133+亚群具有更高的自我更新能力、胚胎基因表达能力、迁移和入侵能力。RNA干扰介导的下调实验表明，HERV-K在微环境修饰过程中对扩大和维持CD133+黑色素瘤亚群具有决定性作用。同样，非核苷类逆转录酶抑制剂（NNRTIs）依非韦伦和奈韦拉平可有效抑制黑色素瘤细胞中HERV-K的激活，拮抗CD133+亚群扩增，并诱导CD133+细胞选择性高水平凋亡。HERV-K激活促进黑色素瘤细胞表型转换，并且在微环境修饰下扩增和维持具有干性特征的CD133+黑色素瘤细胞是严格需要的。
Melanoma is a heterogeneous tumor in which phenotype-switching and CD133 marker have been associated with metastasis promotion and chemotherapy resistance. CD133 positive (CD133+) subpopulation has also been suggested as putative cancer stem cell (CSC) of melanoma tumor. Human endogenous retrovirus type K (HERV-K) has been described to be aberrantly activated during melanoma progression and implicated in the etiopathogenesis of disease. Earlier, we reported that stress-induced HERV-K activation promotes cell malignant transformation and reduces the immunogenicity of melanoma cells. Herein, we investigated the correlation between HERV-K and the CD133+ melanoma cells during microenvironmental modifications. TVM-A12 cell line, isolated in our laboratory from a primary human melanoma lesion, and other commercial melanoma cell lines (G-361, WM-115, WM-266-4 and A375) were grown and maintained in the standard and stem cell media. RNA interference, Real-time PCR, flow cytometry analysis, self-renewal and migration/invasion assays were performed to characterize cell behavior and HERV-K expression. Melanoma cells, exposed to stem cell media, undergo phenotype-switching and expansion of CD133+ melanoma cells, concomitantly promoted by HERV-K activation. Notably, the sorted CD133+ subpopulation showed stemness features, characterized by higher self-renewal ability, embryonic genes expression, migration and invasion capacities compared to the parental cell line. RNA interference-mediated downregulation experiments showed that HERV-K has a decisive role to expand and maintain the CD133+ melanoma subpopulation during microenvironmental modifications. Similarly, non nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine were effective to restrain the activation of HERV-K in melanoma cells, to antagonize CD133+ subpopulation expansion and to induce selective high level apoptosis in CD133+ cells. HERV-K activation promotes melanoma cells phenotype-switching and is strictly required to expand and maintain the CD133+ melanoma cells with stemness features in response to microenvironmental modifications.