肿瘤基质高硬度微环境中SEMA7A促进肝细胞癌侵袭转移的分子机制研究

The occurrence of local and systemic metastasis is a critical reason for the poor prognosis of Hepatocellular carcinoma (HCC). But the molecular mechanisms underlying the metastasis of HCC remain largely unknown. Studies in recent years demonstrated that SEMA7A played critical roles in development and progression processes of human cancers. However, the expression and biological functions of SEMA7A in HCC and the underlying mechanisms have not been investigated. Preliminary data confirmed that: (1) compared with adjacent non-tumor tissues, HCC tissues showed significantly increased SEMA7A expression; increased expression of SEMA7A in HCC tissues was correlated with poor clinicopathological features of HCC patients; (2) high matrix stiffness could increase SEMA7A expression and P300 protein level in HCC cells; knockdown of P300 decreased SEMA7A expression in HCC cells; 3’-UTR of SEMA7A mRNA contained the complementary sequences for miR-27b-3p binding while high matrix stiffness could decrease the expression level of miR-27b-3p in HCC cells; (3) functionally, SEMA7A was found to enhance the in vitro migration and invasion of HCC cells. Based on these preliminary data, this project will employ molecular biology techniques and animal models to further prove the following hypothesis: (1) high matrix stiffness can upregulate SEMA7A expression transcriptionally by increasing P300 and post-transcriptionally by decreasing miR-27b-3p in HCC cells; (2) SEMA7A in HCC cells can interact with the Integrin-b1 receptor and activate the downstream FAK/AKT pathway, and subsequently enhance the metastatic ability of HCC cells by promoting epithelial-mesenchymal transition and increasing MMP2/9 expression; (3) blocking SEMA7A can prevent the systemic metastasis of HCC cells in vivo. In summary, this project will elucidate the regulatory network by which high matrix-stiffness of tumor microenvironment leads to elevated SEMA7A expression in HCC, and clarify the molecular mechanisms by which SEMA7A promotes the metastasis of HCC, and propose SEMA7A as a novel biomarker and therapeutic target of HCC.

肝细胞癌（HCC）侵袭转移的分子机制复杂，目前仍未探明。研究发现：SEMA7A在多种肿瘤发展过程中发挥重要作用。然而，SEMA7A在HCC中的表达、功能及分子机制仍未见研究。预实验结果提示：SEMA7A在HCC组织中高表达，与不良临床病理特征相关；肿瘤高基质硬度微环境是SEMA7A在HCC中高表达的重要原因；SEMA7A可增强HCC细胞的迁移侵袭能力。因此，本项目拟利用分子生物学技术及动物实验进一步探明：肿瘤高基质硬度微环境可通过上调P300及下调miR-27b-3p分别在转录和转录后水平增加HCC细胞SEMA7A的表达；SEMA7A可激活Integrin-b1/FAK/AKT通路，导致HCC细胞发生EMT及MMP表达增加，继而获得更强的迁移侵袭能力；靶向阻断SEMA7A能够抑制HCC细胞在动物体内侵袭转移的发生。通过上述实验，本项目拟将SEMA7A确定为HCC的新生物学标志物及治疗靶点。

项目背景：肝细胞癌（HCC）生长转移的分子机制复杂，目前仍未探明。研究发现：SEMA7A在多种肿瘤发展过程中发挥重要作用。然而，SEMA7A在HCC中的表达、功能及分子机制仍未见研究。.研究内容：本研究探究了SEMA7A在HCC中的表达情况、表达水平和预后相关性；并探究SEMA7A对HCC细胞生长能力及转移能力的影响。.关键数据：SEMA7A在HCC组织中明显高表达，SEMA7A高表达与HCC患者的不良预后具有相关性。在HCC细胞中过表达SEMA7A后，细胞增殖、迁移及侵袭能力显著增强，间质表型显著增加；敲低SEMA7A后，HCC细胞的增殖、迁移及侵袭能力显著降低，间质表型显著减弱；SEMA7A可激活HCC细胞内的AKT通路；抑制AKT通路后，SEMA7A对HCC细胞生长及转移的促进作用被阻断。在高硬度培养基上的HCC细胞内的SEMA7A表达显著增高，表明肿瘤基质高硬度微环境可能上调SEMA7A在HCC细胞中的表达。.科学意义：本研究初步表明SEMA7A可能通过激活细胞内AKT通路，在HCC发生发展中发挥促癌作用，具有成为肝癌未来治疗靶点的可能性；SEMA7A高表达提示HCC患者不良预后，表明其有望成为HCC患者预后的标志物。肿瘤基质硬度微环境可能是导致HCC中SEMA7A异常高表达的重要驱动因素。

内容获取失败，请点击重试