SOX9触发不同的上皮-间质转化状态以促进胰腺癌进展。
SOX9 Triggers Different Epithelial to Mesenchymal Transition States to Promote Pancreatic Cancer Progression.
作者信息
Carrasco-Garcia Estefania, Lopez Lidia, Moncho-Amor Veronica, Carazo Fernando, Aldaz Paula, Collado Manuel, Bell Donald, Gaafar Ayman, Karamitopoulou Eva, Tzankov Alexandar, Hidalgo Manuel, Rubio Ángel, Serrano Manuel, Lawrie Charles H, Lovell-Badge Robin, Matheu Ander
机构信息
Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain.
CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain.
出版信息
Cancers (Basel). 2022 Feb 12;14(4):916. doi: 10.3390/cancers14040916.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers mainly due to spatial obstacles to complete resection, early metastasis and therapy resistance. The molecular events accompanying PDAC progression remain poorly understood. SOX9 is required for maintaining the pancreatic ductal identity and it is involved in the initiation of pancreatic cancer. In addition, SOX9 is a transcription factor linked to stem cell activity and is commonly overexpressed in solid cancers. It cooperates with Snail/Slug to induce epithelial-mesenchymal transition (EMT) during neural development and in diseases such as organ fibrosis or different types of cancer.
METHODS
We investigated the roles of SOX9 in pancreatic tumor cell plasticity, metastatic dissemination and chemoresistance using pancreatic cancer cell lines as well as mouse embryo fibroblasts. In addition, we characterized the clinical relevance of SOX9 in pancreatic cancer using human biopsies.
RESULTS
Gain- and loss-of-function of SOX9 in PDAC cells revealed that high levels of SOX9 increased migration and invasion, and promoted EMT and metastatic dissemination, whilst SOX9 silencing resulted in metastasis inhibition, along with a phenotypic reversion to epithelial features and loss of stemness potential. In both contexts, EMT factors were not altered. Moreover, high levels of SOX9 promoted resistance to gemcitabine. In contrast, overexpression of SOX9 was sufficient to promote metastatic potential in transformed MEFs, triggering EMT associated with Snail/Slug activity. In clinical samples, SOX9 expression was analyzed in 198 PDAC cases by immunohistochemistry and in 53 patient derived xenografts (PDXs). SOX9 was overexpressed in primary adenocarcinomas and particularly in metastases. Notably, SOX9 expression correlated with high vimentin and low E-cadherin expression.
CONCLUSIONS
Our results indicate that SOX9 facilitates PDAC progression and metastasis by triggering stemness and EMT.
背景
胰腺导管腺癌（PDAC）是最致命的癌症之一，主要原因是完全切除存在空间障碍、早期转移和治疗耐药性。伴随PDAC进展的分子事件仍知之甚少。SOX9是维持胰腺导管特性所必需的，并且参与胰腺癌的起始过程。此外，SOX9是一种与干细胞活性相关的转录因子，在实体癌中通常过度表达。它在神经发育以及器官纤维化或不同类型癌症等疾病中与Snail/Slug协同诱导上皮-间质转化（EMT）。
方法
我们使用胰腺癌细胞系以及小鼠胚胎成纤维细胞研究了SOX9在胰腺肿瘤细胞可塑性、转移扩散和化疗耐药性中的作用。此外，我们通过人体活检来确定SOX9在胰腺癌中的临床相关性。
结果
PDAC细胞中SOX9的功能获得和功能缺失研究表明，高水平的SOX9增加迁移和侵袭，并促进EMT和转移扩散，而SOX9沉默导致转移抑制，同时伴有表型向上皮特征的逆转和干性潜能的丧失。在这两种情况下，EMT因子均未改变。此外，高水平的SOX9促进对吉西他滨的耐药性。相反，SOX9的过表达足以促进转化的MEF中的转移潜能，触发与Snail/Slug活性相关的EMT。在临床样本中，通过免疫组织化学分析了198例PDAC病例和53例患者来源的异种移植瘤（PDX）中的SOX9表达。SOX9在原发性腺癌中尤其是在转移灶中过度表达。值得注意的是，SOX9表达与波形蛋白高表达和E-钙黏蛋白低表达相关。
结论
我们的结果表明，SOX9通过触发干性和EMT促进PDAC进展和转移。
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