Epithelial-mesenchymal transition as a mechanism of resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma
Epithelial-mesenchymal transition as a mechanism of resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma
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DOI：
10.1038/s41374-019-0188-y
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发表时间：
2019-05-01
影响因子：
5
通讯作者：
Cho, Yong Mee
中科院分区：
文献类型：
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作者：
Hwang, Hee Sang;Go, Heounjeong;Cho, Yong Mee
酪氨酸激酶抑制剂（TKI）被广泛接受作为转移性透明细胞肾细胞癌（ccRCC）的治疗。然而，尽管TKI治疗，大多数患者最终仍会发生疾病进展，即使初始缓解良好。为了确定TKI耐药的潜在机制，检查了10例TKI治疗的转移性ccRCC病例，其中在治疗前和疾病进展后立即采集肿瘤样本。研究了匹配的治疗前和治疗后肿瘤样品的基因表达谱和拷贝数变化。在舒尼替尼耐药ccRCC细胞系中证实了生物学特性的改变，这些细胞系是通过用含舒尼替尼的培养基长期处理产生的。与处理前样品相比，处理后的肿瘤样品中与细胞周期和上皮-间质转化（EMT）相关的基因转录水平显著上调。有丝分裂计数和肉瘤样成分在治疗的肿瘤样品中显著增加。在舒尼替尼耐药ccRCC细胞系中也证明了EMT相关基因的改变，与亲本细胞系相比，该细胞系显示出增强的迁移和侵袭。siRNA诱导的EMT相关基因表达的抑制显著抑制了TKI耐药细胞系的迁移和侵袭能力。本研究表明，TKI治疗后进展的ccRCC病例和舒尼替尼耐药ccRCC细胞系均显示EMT相关基因表达的改变和EMT相关行为的增强。这些结果表明，EMT可以解释TKI耐药ccRCC的侵袭行为。
Tyrosine kinase inhibitors (TKIs) are widely accepted as treatment for metastatic clear cell renal cell carcinoma (ccRCC). However, most patients eventually experience disease progression despite TKI treatment, even if the initial response is favorable. To define the underlying mechanism of TKI resistance, 10 TKI-treated metastatic ccRCC cases in which tumor samples were harvested before treatment and immediately after disease progression were examined. Gene expression profiles and copy number variations of matched pre- and post-treatment tumor samples were investigated. Altered biologic characteristics were confirmed in sunitinib-resistant ccRCC cell lines, which were generated by long-term treatment with sunitinib-containing media. Gene transcript levels related to the cell cycle and epithelial-mesenchymal transition (EMT) were significantly upregulated in the treated tumor samples compared with the pre- treatment samples. The mitotic count and sarcomatoid component were significantly increased in treated tumor samples. Alteration of EMT-related genes was also demonstrated in a sunitinib-resistant ccRCC cell line that showed enhanced migration and invasion compared to the parent cell line. siRNA-induced inhibition of EMT-related gene expression significantly suppressed the migration and invasion capacity of TKI-resistant cell lines. The present study shows that both ccRCC cases that progressed after TKI treatment and sunitinib-resistant ccRCC cell lines demonstrated alteration of EMT-related gene expression and enhancement of EMT-related behavior. These results suggest that EMT may explain the aggressive behavior of TKI-resistant ccRCC.