Sun Zhigang, Zhang Chi, Wang Tiantian, Shi Peng, Tian Xingsong, Guo Ying
Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
J Cancer Res Ther. 2019;15(4):933-940. doi: 10.4103/jcrt.JCRT_208_19.
Trastuzumab resistance is a major obstacle encountered in human epidermal growth factor receptor 2 (HER2)-positive breast cancer therapy. Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in both tumorigenesis and tumor development. However, whether lncRNAs are associated with trastuzumab resistance is not yet clear.
We evaluated trastuzumab sensitivity in breast cancer cell lines, SKBR3, HCC1954, and MDA-MB-231. We also evaluated H19 expression in these cell lines after treatment with different trastuzumab concentrations. Besides, H19 was downregulated to investigate its role in cell viability and trastuzumab sensitivity and a trastuzumab resistance cell line was cultured to verify the effect of H19 in trastuzumab resistance. Forty-eight HER2-positive breast cancer patients treated with trastuzumab in the first-line setting were selected retrospectively to explore the relationship between H19 expression and tumor-node-metastasis (TNM) stage as well as trastuzumab resistance.
H19 is a trastuzumab-responsive lncRNA and its expression was upregulated in a trastuzumab-resistant breast cancer cell. Downregulation of H19 restored the sensitivity of trastuzumab-resistant cells to this drug. The expression of H19 significantly correlated with TNM stage. Patients with higher expression of H19 showed an evidently shorter progression-free survival than those with low H19 expression. H19 overexpression was negatively correlated to the trastuzumab-therapy response.
Our results provide evidence for the H19-mediated regulation of trastuzumab resistance in HER2-positive breast cancer cells. H19 could act as a potential predictive biomarker for HER2-positive breast cancer patients, and downregulation of H19 could reverse trastuzumab resistance and enhance the inhibitory function of this drug.
曲妥珠单抗耐药是人类表皮生长因子受体2（HER2）阳性乳腺癌治疗中遇到的主要障碍。长链非编码RNA（lncRNAs）已被证实在肿瘤发生和肿瘤发展中发挥重要作用。然而，lncRNAs是否与曲妥珠单抗耐药相关尚不清楚。
我们评估了乳腺癌细胞系SKBR3、HCC1954和MDA-MB-231对曲妥珠单抗的敏感性。我们还评估了用不同浓度曲妥珠单抗处理后这些细胞系中H19的表达。此外，下调H19以研究其在细胞活力和曲妥珠单抗敏感性中的作用，并培养曲妥珠单抗耐药细胞系以验证H19在曲妥珠单抗耐药中的作用。回顾性选择48例一线接受曲妥珠单抗治疗的HER2阳性乳腺癌患者，以探讨H19表达与肿瘤-淋巴结-转移（TNM）分期以及曲妥珠单抗耐药之间的关系。
H19是一种对曲妥珠单抗有反应的lncRNA，其表达在曲妥珠单抗耐药的乳腺癌细胞中上调。下调H19可恢复曲妥珠单抗耐药细胞对该药物的敏感性。H19的表达与TNM分期显著相关。H19表达较高的患者无进展生存期明显短于H19表达低的患者。H19过表达与曲妥珠单抗治疗反应呈负相关。
我们的结果为H19介导的HER2阳性乳腺癌细胞中曲妥珠单抗耐药调控提供了证据。H19可作为HER2阳性乳腺癌患者的潜在预测生物标志物，下调H19可逆转曲妥珠单抗耐药并增强该药物的抑制功能。
