Ergün Sercan, Ulasli Mustafa, Igci Yusuf Ziya, Igci Mehri, Kırkbes Sevil, Borazan Ersin, Balik Ahmet, Yumrutaş Önder, Camci Celalettin, Cakmak Ecir Ali, Arslan Ahmet, Oztuzcu Serdar
Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Şehitkamil, 27310, Gaziantep, Turkey,
Mol Biol Rep. 2015 Feb;42(2):497-505. doi: 10.1007/s11033-014-3793-2. Epub 2014 Oct 16.
MicroRNAs can regulate many biological functions. miR-122-5p has a tumor suppressor function through different molecular pathways. Also, our second hit, ADAM10, targeted by miR-122-5p, is a major determinant of HER2 shedding causing that trastuzumab cannot bind to HER2 receptors. Therefore, our analysis upon ADAM10 expression and miR-122-5p was a good point to understand molecular mechanism of breast cancer. In our study, we investigated the expression profiles of miR-122-5p and its target ADAM10 in 71 breast cancer patients. Immunohistochemical analysis of ER, PR and HER2 gene products was used to categorize tumors in patients. Expression data and immunohistochemical findings were evaluated to comment on the relationship between miR-122-5p and ADAM10. ADAM10 expression was higher in tumor than that of normal tissue but miR-122-5p expression was lower in tumor than that of normal tissue. The expression pattern in HER2+ patients was reverse of the overall result. It can be explained like that miR-122-5p expression increases especially in HER2+ cancer cell to suppress ADAM10 shedding activity on HER2 receptor. However, increase in expression of tumor suppressor miR-122-5p is not enough to inhibit ADAM10. All in all, we can think miR-122-5p as potential regulator of ADAM10 and trastuzumab resistance. Since if we increase miR-122-5p activity together with trastuzumab administration, then HER2+ breast cancer cells may overcome trastuzumab resistance by inhibiting ADAM10 shedding activity on HER2 receptors and increase the efficiency of trastuzumab.
微小RNA可调节多种生物学功能。miR-122-5p通过不同分子途径发挥肿瘤抑制功能。此外，我们的第二个研究对象，即受miR-122-5p靶向的ADAM10，是HER2脱落的主要决定因素，导致曲妥珠单抗无法与HER2受体结合。因此，我们对ADAM10表达和miR-122-5p的分析是了解乳腺癌分子机制的一个良好切入点。在我们的研究中，我们调查了71例乳腺癌患者中miR-122-5p及其靶标ADAM10的表达谱。采用免疫组织化学分析法对患者肿瘤中的ER、PR和HER2基因产物进行分类。对表达数据和免疫组织化学结果进行评估，以阐述miR-122-5p与ADAM10之间的关系。ADAM10在肿瘤中的表达高于正常组织，但miR-122-5p在肿瘤中的表达低于正常组织。HER2阳性患者的表达模式与总体结果相反。这可以解释为，miR-122-5p的表达尤其在HER2阳性癌细胞中增加，以抑制ADAM10对HER2受体的脱落活性。然而，肿瘤抑制性miR-122-5p表达的增加不足以抑制ADAM10。总而言之，我们可以将miR-122-5p视为ADAM10和曲妥珠单抗耐药性的潜在调节因子。因为如果我们在给予曲妥珠单抗的同时增加miR-122-5p的活性，那么HER2阳性乳腺癌细胞可能通过抑制ADAM10对HER2受体的脱落活性来克服曲妥珠单抗耐药性，并提高曲妥珠单抗的疗效。
