Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Shanghai Colorectal Cancer Research Center, Shanghai 200092, China.
Theranostics. 2020 Jan 16;10(5):2327-2341. doi: 10.7150/thno.39740. eCollection 2020.
Collagen and calcium-binding EGF domain-1 (CCBE1) is essential for lymphatic vascular development as it promotes vascular endothelial growth factor C (VEGFC) proteolysis. A recent study reported that CCBE1 was overexpressed in epithelial colorectal cancer (CRC) cells; however, the role of CCBE1 in tumor lymphangiogenesis and the mechanism underlying dysregulated CCBE1 expression in CRC remain undefined. The role of CCBE1 in tumor lymphangiogenesis and lymphatic metastasis was investigated using human lymphatic endothelial cells (HLECs) model , and a hindfoot lymphatic metastasis model . Immunochemistry analysis was performed to assess CCBE1 expression, prognostic value and correlation with clinicopathological characteristics in CRC. The biochemical function and transcriptional regulatory mechanism of CCBE1 were explored by western blot, qPCR, and chromatin immunoprecipitation. : Cancer cell-derived CCBE1 enhances VEGFC proteolysis , facilitates tube formation and migration of HLECs , and promotes tumor lymphangiogenesis and lymphatic metastasis . In addition to CRC cells, tumor stroma within CRC tissue shows high CCBE1 expression, which is associated with high lymphatic vessel density, increased lymph node metastasis and poor prognosis. Cancer-associated fibroblasts (CAFs) express and secret CCBE1, thereby contributing to VEGFC maturation and tumor lymphangiogenesis in CRC. Transforming growth factor beta (TGF-β) downregulates the transcription and lymphangiogenic function of CCBE1 in CAFs and CRC cells through direct binding of SMADs to CCBE1 gene locus. Inactivation of the TGF-β pathway correlates with increased CCBE1 expression in CRC. : Our results demonstrate the protumorigenic role of CCBE1 in promoting lymphangiogenesis and lymphatic metastasis in CRC, revealing a new mechanism by which loss of TGF-β signaling promotes CRC metastasis.
胶原蛋白和钙结合表皮生长因子结构域 1（CCBE1）是淋巴管生成所必需的，因为它可促进血管内皮生长因子 C（VEGFC）的蛋白水解。最近的一项研究报道 CCBE1 在结直肠癌细胞（CRC）中过表达；然而，CCBE1 在肿瘤淋巴管生成中的作用以及 CRC 中 CCBE1 表达失调的机制仍未阐明。本研究通过人淋巴管内皮细胞（HLEC）模型和后足淋巴管转移模型，研究了 CCBE1 在肿瘤淋巴管生成和淋巴转移中的作用。免疫组织化学分析用于评估 CCBE1 在 CRC 中的表达、预后价值及其与临床病理特征的相关性。通过 Western blot、qPCR 和染色质免疫沉淀实验探索了 CCBE1 的生化功能和转录调控机制。结果表明：癌细胞来源的 CCBE1 增强了 VEGFC 的蛋白水解，促进了 HLEC 的管形成和迁移，并促进了肿瘤淋巴管生成和淋巴转移。除了 CRC 细胞，CRC 组织中的肿瘤基质也表现出高 CCBE1 表达，与高淋巴管密度、淋巴结转移增加和预后不良相关。肿瘤相关成纤维细胞（CAFs）表达并分泌 CCBE1，从而有助于 CRC 中 VEGFC 的成熟和肿瘤淋巴管生成。转化生长因子-β（TGF-β）通过 SMAD 直接结合 CCBE1 基因座下调 CAFs 和 CRC 细胞中 CCBE1 的转录和淋巴管生成功能。TGF-β 通路失活与 CRC 中 CCBE1 表达增加相关。研究结果表明 CCBE1 在促进 CRC 淋巴管生成和淋巴转移中具有促肿瘤作用，揭示了 TGF-β 信号丢失促进 CRC 转移的新机制。
