LncRNA CCAT2通过影响Periostin表达参与调控胃癌侵袭转移的机制研究

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps. Although cancer cells may enter the circulation and egress into distant tissues by the millions, only a small population of cancer stem cells (CSCs) manages to successfully initiate metastatic growth, a process termed ‘metastatic colonization’. Metastatic niches contribute to the survival and fitness of metastasis-initiating CSC in otherwise inhospitable tissue environments. The components of metastatic niches have remained a matter of conjecture, but recent reports point at the extracellular matrix protein periostin as one of the key metastatic niche molecules. By enhancing Wnt signalling in cancer cells, periostin provides a physical as well as signaling support for metastasis-initiating CSCs. Meanwhile, long non-coding RNAs (lncRNAs), a class of transcripts more than 200 nucleotides in length without protein-coding ability, have been reported to play key roles in human tumorigenesis in addition to short microRNAs. In our previous study, we conducted genome-wide lncRNA screening analysis in two sets of clinical samples and identified five plasma lncRNAs as a set of novel diagnostic biomarkers for gastric cancer detection. CCAT2, for instance, is highly overexpressed in various tumors, including colorectal and gastric cancers. CCAT2 also up-regulates MYC, miR–17–5p, and miR–20a expression through TCF7L2-mediated transcriptional regulation. Given these evidence together with its tissue and stage specificity, CCAT2 can serve as a valuable biomarker and potential therapeutic targets for gastric cancer progression. Here, we aimed to explore the roles of periostin in gastric metastasis, and determine that periostin -mediated stromal niche formation was critical for the modulation of gastric cancer cells’ plasticity and fate determination. Then, to test the hypothesis that CCAT2 can be used as an regulatory target for gastric cancer growth and metastasis, we investigated the physiological function and mechanism of CCAT2 associated with periostin, and its involvement in stromal niche formation and the maintenance of gastric CSCs. The new roles of CCAT2 as an upstream regulatory element of periostin help to underscore the importance of developmental and cell survival pathways in gastric metastasis, and provide a novel strategy for the treatment of metastatic disease.

肿瘤干细胞诱导Periostin合成、驯化宿主器官形成定植壁龛是决定肿瘤转移成败的关键步骤。前期工作中我们在胃癌中筛选出5个具有诊断指示功能的LncRNA，其中CCAT2与患者的临床病理特征紧密相关，且可能是Periostin的上游调控元件。由此提出科学问题：借助CCAT2同时干预胃癌干细胞及其赖以生存的微环境，降低远端宿主器官对胃癌干细胞的收容能力。本项目围绕胃癌干细胞和肿瘤微环境的依存关系展开研究。首先，明确Periostin诱导定植壁龛形成及其在胃癌侵袭转移过程中的地位，描述Periostin调控胃癌细胞行为及命运转归的分子机制。随后，以小分子靶点介入研究CCAT2对诱导定植壁龛形成、控制胃癌细胞行为改变的影响，阐明CCAT2与Periostin之间的相互联系。本研究对预防和阻止胃癌转移意义重大，为提高靶向药物识别胃癌微小转移灶的特异性提供理论参考。

肿瘤干细胞诱导Periostin合成、驯化宿主器官形成定植壁龛是决定肿瘤转移成败的关键步骤。基于此，我们提出如下科学假设：敲低Periostin在胃癌细胞内的表达可能遏制其侵袭、转移能力，削弱远端宿主器官对胃癌高侵袭性细胞的收容性，降低胃癌转移细胞和肿瘤微环境的依存紧密度。进一步地，在前期工作中我们发现lncRNA CCAT2与患者的临床病理特征紧密相关，且可能参与胃癌的恶性进展。由此提出科学问题：借助干预胃癌侵袭性细胞及其赖以生存的微环境，降低远端宿主器官对胃癌干细胞的收容能力。本项目以Periostin作为切入点，围绕胃癌细胞和肿瘤微环境的依存关系展开研究。我们借助慢病毒包装干扰技术和体内外恶性生物学行为表型实验明确了Periostin诱导定植壁龛形成及其在胃癌侵袭转移过程中的地位，利用生物信息学分析，初步构建了以Periostin为中心的胃癌恶性进展以及命运转归的调控网络，阐明了Periostin与Wnt/β-catenin通路的调控关系。为深入探索胃癌干细胞介导肿瘤侵袭行为的相关机制，我们利用iTRAQ技术筛选干性转化中的关键分子。随后我们基于临床样本，进一步阐明lncRNA CCAT2与Periostin之间的相互联系。本研究为探索胃癌的发生发展机制，尝试从空间立体范围内多层次、多靶点地调控胃癌进展过程中各细胞组分的行为及命运转归提供了理论依据。