Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA.
Cancer Lett. 2022 Feb 1;526:155-167. doi: 10.1016/j.canlet.2021.11.016. Epub 2021 Nov 23.
Obscurins, encoded by the OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. Large scale omics analyses reveal that OBSCN is highly mutated across different types of cancer, exhibiting a 5-8% mutation frequency in pancreatic cancer. Yet, the functional role of OBSCN in pancreatic cancer progression and metastasis has to be delineated. We herein show that giant obscurins are highly expressed in normal pancreatic tissues, but their levels are markedly reduced in pancreatic ductal adenocarcinomas. Silencing of giant obscurins in non-tumorigenic Human Pancreatic Ductal Epithelial (HPDE) cells and obscurin-expressing Panc5.04 pancreatic cancer cells induces an elongated, spindle-like morphology and faster cell migration via cytoskeletal remodeling. Specifically, depletion of giant obscurins downregulates RhoA activity, which in turn results in reduced focal adhesion density, increased microtubule growth rate and faster actin dynamics. Although OBSCN knockdown is not sufficient to induce de novo tumorigenesis, it potentiates tumor growth in a subcutaneous implantation model and exacerbates metastasis in a hemispleen murine model of pancreatic cancer metastasis, thereby shortening survival. Collectively, these findings reveal a critical role of giant obscurins as tumor suppressors in normal pancreatic epithelium whose loss of function induces RhoA-dependent cytoskeletal remodeling, and promotes cell migration, tumor growth and metastasis.
obscurins，由 OBSCN 基因编码，是具有结构和调节作用的巨大细胞骨架蛋白。大规模组学分析表明，OBSCN 在不同类型的癌症中高度突变，在胰腺癌中表现出 5-8%的突变频率。然而，OBSCN 在胰腺癌进展和转移中的功能作用尚待阐明。我们在此表明，巨大 obscurins 在正常胰腺组织中高度表达，但在胰腺导管腺癌中其水平明显降低。在非肿瘤性人胰腺导管上皮 (HPDE) 细胞和 obscurin 表达的 Panc5.04 胰腺癌细胞中沉默 giant obscurins 会诱导细胞形态拉长、呈纺锤形，并通过细胞骨架重塑导致更快的细胞迁移。具体而言， giant obscurins 的缺失会下调 RhoA 活性，从而导致焦点黏附密度降低、微管生长速度增加和肌动蛋白动力学加快。尽管 OBSCN 敲低不足以诱导新的肿瘤发生，但它在皮下植入模型中增强了肿瘤生长，并在胰腺癌转移的半脾小鼠模型中加剧了转移，从而缩短了生存时间。总之，这些发现揭示了 giant obscurins 在正常胰腺上皮中作为肿瘤抑制因子的关键作用，其功能丧失会诱导 RhoA 依赖性细胞骨架重塑，并促进细胞迁移、肿瘤生长和转移。
