Institute for Cancer Genetics, Columbia University, New York, NY, USA.
Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
Nat Commun. 2023 Mar 10;14(1):1328. doi: 10.1038/s41467-023-36713-8.
The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.
TINCR（终端分化诱导的非编码 RNA）基因在上皮组织中特异性表达，参与人类表皮分化和伤口愈合的调控。尽管最初报道为长非编码 RNA，但 TINCR 基因座编码与角质形成细胞分化相关的高度保守的泛素样微蛋白。在这里，我们报告了 TINCR 作为鳞状细胞癌（SCC）中的肿瘤抑制因子的鉴定。TINCR 在人角质形成细胞中由 UV 诱导的 DNA 损伤以 TP53 依赖性方式上调。在皮肤和头颈部鳞状细胞肿瘤中普遍发现 TINCR 蛋白表达降低，TINCR 表达抑制 SCC 细胞在体外和体内的生长。一致地，Tincr 敲除小鼠在 UVB 皮肤致癌作用后表现出肿瘤发展加速和侵袭性 SCC 的渗透率增加。最后，遗传分析鉴定了 SCC 临床样本中包含 TINCR 基因的功能丧失突变和缺失，支持其在人类癌症中作为肿瘤抑制因子的作用。总之，这些结果表明 TINCR 作为蛋白质编码肿瘤抑制基因在鳞状细胞癌中反复丢失。
