Wang Jichuan, Sato Kenji, O'Donnell Ed, Singla Amit, Yaguare Simon, Aldahamsheh Osama, Batko Brian, Borjihan Hasibagan, Tingling Janet, Zhang Jinghang, Weiser Daniel A, Loeb David M, Gorlick Richard, Schwartz Edward L, Yang Rui, Zi Xiaolin, Zhao Hongling, Geller David S, Hoang Bang H
Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Musculoskleletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People's Hospital, Beijing, China.
Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
Transl Oncol. 2020 Oct;13(10):100809. doi: 10.1016/j.tranon.2020.100809. Epub 2020 Jul 2.
Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.
滑膜肉瘤（SS）是一种侵袭性软组织癌，预后较差，易于局部复发和远处转移。在本研究中，我们调查了S期激酶相关蛋白（Skp2）在SS的肿瘤起始、进展和转移中是否发挥致癌作用。我们的研究表明，Skp2在SS标本和SS18-SSX转基因小鼠肿瘤中经常过度表达，并且与临床分期相关。接下来，我们发现Skp2的基因缺失降低了间充质和干性标志物，并抑制了SS细胞系的侵袭和增殖能力。此外，Skp2缺失显著抑制了SS异种移植肿瘤的生长。用Skp2抑制剂黄酮卡瓦因A（FKA）处理SS细胞系以剂量依赖性方式降低Skp2表达，并导致细胞周期停滞和凋亡。FKA还抑制了SS中的侵袭和肿瘤起始特性，类似于Skp2敲低的效果。此外，FKA与传统化疗的联合显示出协同治疗效果。综上所述，我们的结果表明Skp2通过促进间充质状态和癌症干性在SS生物学中发挥重要作用。鉴于化疗耐药性通常与癌症干性相关，在SS中将Skp2抑制剂与传统化疗联合的策略可能是可取的。
