Gunarta I Ketut, Li Rong, Nakazato Ryota, Suzuki Ryusuke, Boldbaatar Jambaldorj, Suzuki Takeshi, Yoshioka Katsuji
Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Division of Functional Genomic, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Cancer Sci. 2017 Aug;108(8):1602-1611. doi: 10.1111/cas.13294. Epub 2017 Jul 11.
Cutaneous melanoma is the most aggressive form of skin cancer. This aggressiveness appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non-invasive and invasive potential, and microphthalmia-associated transcription factor (MITF) is known to play a central role in this process. The transcription factor glioma-associated oncogene homolog 1 (GLI1) is a component of the canonical and noncanonical sonic hedgehog pathways. Although GLI1 has been suggested to be involved in melanoma progression, its precise role and the mechanism underlying invasion remain unclear. Here we investigated whether and how GLI1 is involved in the invasive ability of melanoma cells. Gli1 knockdown (KD) melanoma cell lines, established by using Gli1-targeting lentiviral short hairpin RNA, exhibited a markedly reduced invasion ability, but their MITF expression and activity were the same as controls. Gli1 KD melanoma cells also led to less lung metastasis in mice compared with control melanoma cells. Furthermore, the Gli1 KD melanoma cells underwent a mesenchymal-to-epithelial-like transition, accompanied by downregulation of the epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (EMT-TF) Snail1, Zeb1 and Twist1, but not Snail2 or Zeb2. Collectively, these results indicate that GLI1 is important for maintaining the invasive and mesenchymal-like properties of melanoma cells independent of MITF, most likely by modulating a subset of EMT-TF. Our findings provide new insight into how heterogeneity and plasticity are achieved and regulated in melanoma.
皮肤黑色素瘤是皮肤癌中侵袭性最强的一种形式。这种侵袭性似乎归因于癌细胞能够在具有非侵袭性和侵袭性潜能的表型之间可逆地转换，并且已知小眼畸形相关转录因子（MITF）在这一过程中发挥核心作用。转录因子胶质瘤相关致癌基因同源物1（GLI1）是经典和非经典音猬因子信号通路的一个组成部分。尽管有人提出GLI1参与黑色素瘤进展，但其确切作用以及侵袭的潜在机制仍不清楚。在此，我们研究了GLI1是否以及如何参与黑色素瘤细胞的侵袭能力。通过使用靶向Gli1的慢病毒短发夹RNA建立的Gli1敲低（KD）黑色素瘤细胞系表现出侵袭能力显著降低，但其MITF表达和活性与对照相同。与对照黑色素瘤细胞相比，Gli1 KD黑色素瘤细胞在小鼠体内也导致较少的肺转移。此外，Gli1 KD黑色素瘤细胞经历了间充质到上皮样转变，伴随着上皮-间充质转化（EMT）诱导转录因子（EMT-TF）Snail1、Zeb1和Twist1的下调，但Snail2或Zeb2未下调。总的来说，这些结果表明GLI1对于维持黑色素瘤细胞的侵袭性和间充质样特性很重要，且不依赖于MITF，最有可能是通过调节一部分EMT-TF来实现的。我们的发现为黑色素瘤中如何实现和调节异质性及可塑性提供了新的见解。
