Department of Oncology Surgery, First Affiliated Hospital of BengBu Medical College, BengBu city, AnHui province, China.
Asian Pac J Cancer Prev. 2021 Nov 1;22(11):3693-3703. doi: 10.31557/APJCP.2021.22.11.3693.
IGF1R and HER2 are both members of the growth factor receptor family which is known to play a different role in breast cancer. However, correlation between IGF1R and HER2 has created a controversial situation that need to be fully delineated in development of Herceptin resistance. The aim of this study was to investigate the mechanism of Herceptin resistance through the IGF1R pathway in HER2 positive breast cancer.
Clinical data were obtained from TCGA database and archived documents from The First Affiliated Hospital of Bengbu Medical College. Western blot and immunohistochemistry were used to detect proteins and their phosphorylation. Cell transfection were constructed using shRNA lentivirus vectors. RNAs were analyzed by RT-qPCR. Proteins in serum were analyzed by ELISA assay. Cell proliferation was analyzed by MTS method. Luciferase report experiment was conducted to verify RNA's inter-reaction.
Western blot showed IGF2 protein was significantly increased in Herceptin resistant SKBR3-R cells (P<0.01), and IGF1R/HER2 heterodimer level was significantly increased (P<0.01). Luciferase reporter assay verified miR-98-5p could bind to 3 'UTR of IGF2 mRNA. When miR-98-5p was upregulated, the expression level of IGF2 was decreased(P<0.01), the cell invasive ability was reduced(P<0.01), and ultimately, Herceptin resistant cells regained their sensitivity to Herceptin. In clinical research, we found that decreased miR-98-5p level or increased IGF2 level significantly associated with poor treatment response and poor overall survival (OS), poor recurrence free survival (RFS) and poor distant metastasis-free survival (DMFS) in HER2-positive breast cancer.
MiR-98-5p and IGF2 might potential candidates for predicting Herceptin sensitivity and provides a new way to overcome Herceptin resistance in clinic.
IGF1R 和 HER2 均属于生长因子受体家族成员，它们在乳腺癌中的作用不尽相同。然而，IGF1R 与 HER2 的相关性导致了一种有争议的情况，需要在曲妥珠单抗耐药的发展过程中进行充分描述。本研究旨在通过研究 IGF1R 通路探讨 HER2 阳性乳腺癌曲妥珠单抗耐药的机制。
从 TCGA 数据库和蚌埠医学院第一附属医院的存档文件中获取临床数据。使用 Western blot 和免疫组化检测蛋白及其磷酸化水平。使用 shRNA 慢病毒载体构建细胞转染。通过 RT-qPCR 分析 RNA。通过 ELISA 测定血清中的蛋白质。通过 MTS 法分析细胞增殖。通过荧光素酶报告实验验证 RNA 的相互作用。
Western blot 显示，在曲妥珠单抗耐药的 SKBR3-R 细胞中 IGF2 蛋白显著增加（P<0.01），IGF1R/HER2 异二聚体水平显著增加（P<0.01）。荧光素酶报告实验证实 miR-98-5p 可以与 IGF2 mRNA 的 3'UTR 结合。当 miR-98-5p 上调时，IGF2 的表达水平降低（P<0.01），细胞侵袭能力降低（P<0.01），最终使曲妥珠单抗耐药细胞恢复对曲妥珠单抗的敏感性。在临床研究中，我们发现 miR-98-5p 水平降低或 IGF2 水平升高与 HER2 阳性乳腺癌患者治疗反应不良、总生存期（OS）不良、无复发生存期（RFS）不良和无远处转移生存期（DMFS）不良显著相关。
miR-98-5p 和 IGF2 可能是预测曲妥珠单抗敏感性的潜在候选物，并为临床克服曲妥珠单抗耐药提供了新的途径。
