Background: Early events in the progression of 90%of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pat...
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Background: Early events in the progression of 90%of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pathways in colonic epithelial cell differentiation. Aims: To investigate whether expression of Gli1, a transactivator of Hh signalling, can suppress Wnt signalling and inhibit proliferation of human colorectal cancer cells. Methods: Gli1 and nuclear β-catenin expression were examined in a series of 40 human colorectal cancers by immunohistochemistry. We quantified Gli1 and nuclear β-catenin staining as markers of Hh and Wnt pathway activation, respectively. Two human colon cancer cell lines, SW480 and HCT116, with mutations in APC and β-catenin, respectively, were used. The effects of Gli1 overexpression on Wnt transcriptional activity, β-catenin subcellular distribution, and proliferation in these cells were analysed. Results: Nuclear accumulation of β-catenin and the Gli1 staining level were inversely associated in the 40 human colorectal cancers. Wnt transcriptional activity was reduced in Gli1 transfected cells. These effects were observed even in Gli1 transfected cells cotransfected with mutated β-catenin. Furthermore, nuclear accumulation of β-catenin was diminished compared with that in empty vector transfected cells, and downregulated transcription of c-Myc was observed in Gli1 transfected cells. Proliferation of Gli1 transfected cells was also significantly suppressed compared with that in empty vector transfected cells. Conclusions: Our data suggest that Gli1 plays an inhibitory role in the development of colorectal cancer involving Wnt signalling, even in cases with the stabilising mutation of β-catenin.
本发明涉及一种具有抑制人结直肠癌细胞增殖作用的重组蛋白的制备与应用，该重组蛋白名称为Amuc_1434，具有抑制人结直肠癌细胞(SW480和HCT‑116)增殖作用。重组蛋白Amuc_1434来源于肠道菌Akkermansia muciniphila ATCC BAA‑835，其氨基酸序列如SEQ ID NO：1所示，基因序列如SEQ ID NO：2所示。经外源表达的重组蛋白Amuc_1434具有抑制结直肠癌细胞增殖及诱导肠癌细胞凋亡的功能，且不会影响正常细胞的活性。除此之外，重组蛋白Amuc_1434与奥沙利铂联合使用可有效提升奥沙利铂对结直肠癌细胞的增殖抑制的效果，增强结直肠癌耐药细胞对奥沙利铂的药物敏感性。Amuc_1434在制备用于治疗或辅助治疗人类结直肠癌的重组蛋白药物上具有潜在的应用价值以及广阔的应用前景。
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