肿瘤相关巨噬细胞通过Galectin-1-MYO1B途径促进结直肠癌侵袭转移的分子机制

Tumor-associated macrophages (TAMs) play important roles in invasion and metastasis in tumor environment. We confirmed that TAMs were mainly M2 macrophages in colorectal cancer (CRC). Galectin-1 secreted by TAMs may promote the invasion and metastasis of CRC. Moreover, we identified MYO1B as the target protein of galectin-1. Based on our experimental data, we propose that TAMs promote invasion and metastasis via Galectin-1-MYO1B pathway in CRC. In order to confirm our hypothesis, the expression of TAM markers, galectin-1, MYO1B, and EMT markers in CRC will be detected, Galectin-1-/- transgenic mice and CRC metastatic models of nude mice will be established. Co-immunoprecipitation, farwestern, immune electron microscopy and GST-pull down assay will be adapted to explore the Galectin-1-MYO1B interaction sites and biological functions. In summary, our study will contribute to more effective CRC therapy targeting for TAMs.

肿瘤相关巨噬细胞（Tumor-associated macrophage, TAM）在肿瘤微环境中的作用和调控机制是当前研究热点。前期研究发现结直肠癌中TAM为具独特免疫表型的M2型巨噬细胞，TAM分泌的Galectin-1因子与结直肠癌侵袭转移相关，且初步鉴定MYO1B为Galectin-1因子位于癌细胞的靶蛋白。因此我们提出TAM通过调控Galectin-1-MYO1B途径促进结直肠癌侵袭转移的研究假说。本课题拟进一步通过组织标本分析、体外原代细胞学实验、建立Galectin-1基因敲除小鼠及结直肠癌裸鼠转移模型等方法证实TAM通过Galectin-1-MYO1B途径促进结直肠癌侵袭和转移；并采用IP、farwestern、免疫电镜和GST-pull down等技术明确二者相互作用关系及作用机制，为以TAM为靶标的肿瘤微环境治疗提供新的思路。

结直肠癌转移是导致患者死亡的重要原因。肿瘤相关巨噬细胞（TAMs）在多种肿瘤中与肿瘤发生、转移和治疗反应密切相关。但有关TAMs在结直肠癌中的功能及临床意义仍不明确。本研究中，我们发现位于结直肠癌侵袭前缘的主要为M2型TAMs，TAMs分泌大量因子从而促进结直肠癌侵袭转移。Galectin-1是其中一种重要因子，它可以与侵袭前缘的结直肠癌细胞的MYO1B蛋白结合，通过旁分泌的Galectin-1-MYO1B-RACK1信号通路，促进上皮间质转化，骨架重组，丝状伪足和侵袭性伪足的形成，阻断该通路则抑制结直肠癌细胞的运动及侵袭。因此，我们的结果揭示了TAMs在结直肠癌中的重要作用，强调了靶向M2型TAMs的重要性，提出了干预galectin-1-MYO1B-RACK1信号通路可以作为治疗结直肠癌的新策略。