4.1N与EGFR作用抑制乳腺癌发生和去分化的机制研究

Poorly differentiate breast cancer has a worsening prognosis and high metastasis. The forming mechanism is unclear up to now. So the research on it is very significant for the cancer therapy. We have found that: Protein 4.1N was tightly connected with the cancer dedifferentiation. 4.1N was lost in the poorly differentiate breast cancer. The cancer cell would be apoptosis and suppressed in proliferation when 4.1N was expressed in this kind of cells, and the changing of the signal pathway showed that EGFR and its downstream signal pathway proteins were suppressed. Then it was found that EGFR and 4.1N could interact with each other. Over activated EGFR is one important reason that cancer cells have epithelial-mesenchymal transition and dedifferentiation, thus cancer cells presented the the reverse epithelial-mesenchymal transition when 4.1N expressed in the 4.1N deficient cancer cell line. Based on the previous finding, we will deeply study in the interaction of 4.1N and EGFR, and in the epithelial-mesenchymal transition. The changing will be clarified on the cells' proliferation, apoptosis, form, movement, metastasis and so forth because of the inhibition of EGFR by 4.1N. The mechanism of 4.1N suppressing breast cancer will be illustrated finally. And it will be very valuable and supply the basic theory in developing the anti-cancer drug.

低分化乳腺癌恶性程度高、转移性强，形成机制至今尚未清楚，其研究对治疗和控制肿瘤具有重要的理论和应用意义。我们前期研究发现：4.1N蛋白与癌细胞分化具有显著的关联，低分化乳腺癌细胞4.1N表达缺失，引入4.1N可抑制其增殖、促进凋亡；检测相关信号蛋白发现，EGFR及其下游信号途径被抑制；进一步研究发现4.1N与EGFR存在蛋白相互作用。同时发现，引入4.1N的低分化癌细胞出现上皮到间质转化的逆转，与EGFR活性受到抑制有关。本研究拟在前期原创性研究基础上，深入研究4.1N与EGFR相互作用抑制乳腺癌发生，及对乳腺癌细胞上皮到间质转化和去分化的影响。通过分子生物学、细胞生物学等手段对两基因相互作用对乳腺癌细胞在增殖、凋亡、形态、运动、迁移等特征的变化进行揭示，最终阐明4.1N基因在癌细胞发生和去分化过程中的独特作用，对研发新型的抗癌药物提供重要的理论与应用基础。该研究目前在国际上尚未见报道。

我们研究发现：4.1N蛋白与癌细胞分化具有显著的关联，低分化乳腺癌细胞4.1N表达缺失，引入4.1N可抑制其增殖、促进凋亡；检测相关信号蛋白发现，EGFR及其下游信号途径被抑制；进一步研究发现4.1N与EGFR存在蛋白相互作用。同时发现，引入4.1N的低分化癌细胞出现上皮到间质转化的逆转，与EGFR活性受到抑制有关。在本项目支持下，深入研究了4.1N与EGFR相互作用抑制乳腺癌发生，及对乳腺癌细胞上皮到间质转化和去分化的影响。我们研究发现，4.1N对EGFR有明显的抑制作用，分子水平上，4.1N可抑制EGFR的二聚体化，并且明显抑制EGFR在膜上的运动能力；研究发现，作为重要的抑癌基因，4.1N对乳腺癌细胞的抑制作用主要发生在增殖阶段，不影响凋亡，可抑制细胞的运动和迁移。裸鼠实验同样发现，4.1N基因可显著抑制瘤的发生，进一步说明了4.1N基因是重要的抑癌基因。因此，对此基因的研究可为研发新型的抗癌药物提供重要的理论与应用基础。