Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Via Moruzzi, 1, 56124, Pisa, Italy.
Division of Medical Genetics, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
J Exp Clin Cancer Res. 2019 Mar 1;38(1):108. doi: 10.1186/s13046-019-1116-0.
Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate.
Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq.
Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation.
Collectively, these results support a role of defective cohesin in the development of human colorectal cancer.
癌细胞的特征是染色体不稳定（CIN），人们认为参与忠实染色体分离的途径中的错误在 CIN 的发生中起着关键作用。黏合蛋白形成一个大的蛋白质环，通过环绕它们来结合 DNA 链。除了在染色体分离中的核心作用外，黏合蛋白还需要用于 DNA 修复、基因转录调控和染色质结构。尽管在许多人类癌症中已经鉴定出黏合蛋白和黏合蛋白调节基因的突变，但黏合蛋白对癌症发展的贡献仍存在争议。
通过 OncoScan 分析来自 16 例结直肠癌（CRC）患者的正常黏膜、早期腺瘤和癌组织样本，以评分染色体增益和丢失（CNVs）和杂合性丢失（LOH）。然后，通过免疫化学分析 66 例 CRC 患者的 SMC1A 表达。在免疫缺陷小鼠模型中分析 SMC1A 过表达和突变 SMC1A 的作用。最后，我们通过 RNA-seq 测量了诱导肿瘤中的全基因表达谱。
在这里，我们表明 SMC1A 黏合蛋白核心基因在人类结直肠癌中存在额外拷贝、突变和过表达。然后，我们证明黏合蛋白过表达通过基因表达失调导致免疫缺陷小鼠中侵袭性癌症的发展。
综上所述，这些结果支持黏合蛋白缺陷在人类结直肠癌发展中的作用。
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