癌基因HOXC10多层面调控肺腺癌转移及其作用机制研究

Distant metastasis is the most vital contributor to the deaths of cancer patients. Epithelial-mesenchymal transition(EMT) and cancer stem cell(CSC)-like traits are closely associated with cancer recurrence and metastasis.Hence, it plays important role for tumor therapy and prognosis to identify key molecules and validate the underlying mechanisms in regulating cancer distant metastasis. Previously, through bioinformatic analysis of lung adenocarcinoma datasets in the Cancer Genome Atlas (TCGA) and biological assays, we found that HOXC10 was overexpressed in lung adenocarcinoma, and HOXC10 expression was significantly higher in recurrent and metastatic lung adenocarcinoma samples. Importantly, higher HOXC10 expression was found to be associated with shorter overall survival and poorer relapse-free survival in lung adenocarcinoma. Furthermore, our recent preliminary in vivo data showed that upregulation of HOXC10 induced distant metastasis and promoted cancer stem cell-like traits in lung adenocarcinoma. Meanwhile, HOXC10 positively associated with TCF1, which is a key downstream effect gene of Wnt/β-catenin signaling pathway, and transcriptionally promoted TGF-β pathway through binding to the promotor of SMAD3,but it is necessary to further study and clarify its mechanisms. In the current project, we will explore the biological functions and underlying molecular mechanisms of HOXC10-induced lung adenocarcinoma distant metastasis, which might provide novel therapeutic target for lung adenocarcinoma distant metastasis.

肿瘤转移是恶性肿瘤致死最重要的因素，而上皮-间质转化（EMT）和肿瘤干细胞特性与肿瘤转移密切相关。前期通过生物信息学和生物化学实验，我们发现：①HOXC10在肺腺癌患者中表达上调，且与局部复发和转移显著相关；②HOXC10与肺腺癌患者的五年总生存和无复发生存预后呈负相关。进一步体内预实验结果显示：上调HOXC10可促进肺腺癌细胞发生脑转移和骨转移；增强肺腺癌细胞的肿瘤干细胞特性。同时我们发现：HOXC10与Wnt/β-catenin信号通路的关键效应因子TCF1表达正相关；HOXC10通过促进SMAD3的转录激活TGF-β信号通路，但具体机制尚待阐明。本项目将承上启下，以稳定高表达和低表达HOXC10细胞为模型，结合老鼠心内转移模型、免疫共沉淀等实验手段，从生物学功能、作用机制及临床意义三个方面，深层次解析癌基因HOXC10促进肺腺癌转移的具体机制，为肺腺癌转移提供新的治疗靶点。

肿瘤转移是恶性肿瘤的主要特征，是导致肿瘤患者死亡的最主要因素。肺癌是全球最常见的恶性肿瘤之一，其死亡率居世界第一，发病率居世界第二；而在中国，其发病率和死亡率均高居第一。肺腺癌作为肺癌主要病理类型，其高侵袭和转移力是导致临床治疗失败和预后不良的主要原因，即使早期肺腺癌原发肿瘤经过根治性切除治疗，仍有超过半数的患者会出现局部复发和转移，且转移性肺腺癌患者的5年生存率低于5%。因此，深入探究肺腺癌转移的分子机制，寻找肿瘤细胞转移过程中关键分子及信号通路并进行进一步针对性干预，将为恶性肿瘤的预防和治疗提供潜在靶点。. HOXC10属于HOX基因家族C簇，研究表明，HOXC10在多种肿瘤中表达上调，并且可能通过诱导肿瘤细胞的侵袭或者转移促进肿瘤的恶性进展。而HOXC10是否参与肺腺癌的恶性进展及其作用机制，尚需进一步研究。我们的研究证实，HOXC10在肺腺癌的组织和细胞系中显著高表达，并且与远处转移密切相关。生信分析和临床标本结果表明，HOXC10高表达的肺腺癌患者无转移生存预后差于HOXC10低表达的患者，可以作为肺腺癌患者预后的一个独立指标。体内外功能性实验表明，高表达HOXC10促进，而沉默HOXC10抑制肺腺癌细胞的转移能力。进一步深入研究发现，HOXC10高表达的肺腺癌患者中VEGFA的表达较高，而HOXC10低表达的肺腺癌患者中VEGFA表达较低。并且，HOXC10的表达与循环肿瘤细胞的数目呈正相关。本项目从细胞、分子生物学、动物实验以及临床标本等多方面深层次剖析癌基因HOXC10促进肺腺癌远处转移的生物学功能和作用机制，并进一步与临床样本结合，验证HOXC10是否可以作为干预肺腺癌转移的潜在靶点。