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PTPN11 Knockdown Prevents Changes in the Expression of Genes Controlling Cell Cycle, Chemotherapy Resistance, and Oncogene-Induced Senescence in Human Thyroid Cells Overexpressing BRAF V600E Oncogenic Protein
Biochemistry (Moscow) ( IF 2.3 ) Pub Date : 2020-01-01 , DOI: 10.1134/s0006297920010101
L. V. Putlyaeva , D. E. Demin , A. N. Uvarova , L. S. Zinevich , M. M. Prokofjeva , G. R. Gazizova , E. I. Shagimardanova , A. M. Schwartz

The MAPK (RAS/BRAF/MEK/ERK) signaling pathway is a kinase cascade involved in the regulation of cell proliferation, differentiation, and survival in response to external stimuli. The V600E mutation in the BRAF gene has been detected in various tumors, resulting in a 500-fold increase in BRAF kinase activity. However, monotherapy with selective BRAF V600E inhibitors often leads to reactivation of MAPK signaling cascade and emergence of drug resistance. Therefore, new targets are being developed for the inhibition of components of the aberrantly activated cascade. It was recently discovered that resistance to BRAF V600E inhibitors may be associated with the activity of the tyrosine phosphatase SHP-2 encoded by the PTPN11 gene. In this paper, we analyzed transcriptional effects of PTPN11 gene knockdown and selective suppression of BRAF V600E in a model of thyroid follicular epithelium. We found that the siRNA-mediated knockdown of PTPN11 after vemurafenib treatment prevented an increase in the expression CCNA1 and NOTCH4 genes involved in the formation of drug resistance of tumors. On the other hand, downregulation of PTPN11 expression blocked the transcriptional activation of genes (p21, pl5, pl6, RBI, and IGFBP7) involved in cell cycle regulation and oncogene-induced senescence in response to BRAF V600E expression. Therefore, it can be assumed that SHP-2 participates not only in emergence of drug resistance in cancer cells, but also in oncogene-induced cell senescence.

中文翻译:

PTPN11 敲低可防止过表达 BRAF V600E 致癌蛋白的人类甲状腺细胞中控制细胞周期、化疗耐药性和致癌基因诱导衰老的基因表达发生变化

MAPK (RAS/BRAF/MEK/ERK) 信号通路是一种激酶级联反应,参与调节细胞增殖、分化和响应外部刺激的存活。已在各种肿瘤中检测到 BRAF 基因中的 V600E 突变,导致 BRAF 激酶活性增加 500 倍。然而,选择性 BRAF V600E 抑制剂的单一疗法通常会导致 MAPK 信号级联的重新激活和耐药性的出现。因此,正在开发用于抑制异常激活级联组分的新靶标。最近发现,对 BRAF V600E 抑制剂的耐药性可能与 PTPN11 基因编码的酪氨酸磷酸酶 SHP-2 的活性有关。在本文中,我们在甲状腺滤泡上皮模型中分析了 PTPN11 基因敲低和选择性抑制 BRAF V600E 的转录效应。我们发现在 vemurafenib 治疗后 siRNA 介导的 PTPN11 敲低阻止了参与肿瘤耐药性形成的 CCNA1 和 NOTCH4 基因表达的增加。另一方面,PTPN11 表达的下调阻断了参与细胞周期调节和癌基因诱导衰老的基因(p21、pl5、pl6、RBI 和 IGFBP7)的转录激活,以响应 BRAF V600E 表达。因此,可以假设 SHP-2 不仅参与了癌细胞耐药性的出现,还参与了癌基因诱导的细胞衰老。我们发现在 vemurafenib 治疗后 siRNA 介导的 PTPN11 敲低阻止了参与肿瘤耐药性形成的 CCNA1 和 NOTCH4 基因表达的增加。另一方面,PTPN11 表达的下调阻断了参与细胞周期调节和癌基因诱导衰老的基因(p21、pl5、pl6、RBI 和 IGFBP7)的转录激活,以响应 BRAF V600E 表达。因此,可以假设 SHP-2 不仅参与了癌细胞耐药性的出现,还参与了癌基因诱导的细胞衰老。我们发现在 vemurafenib 治疗后 siRNA 介导的 PTPN11 敲低阻止了参与肿瘤耐药性形成的 CCNA1 和 NOTCH4 基因表达的增加。另一方面,PTPN11 表达的下调阻断了参与细胞周期调节和癌基因诱导衰老的基因(p21、pl5、pl6、RBI 和 IGFBP7)的转录激活,以响应 BRAF V600E 表达。因此,可以假设 SHP-2 不仅参与了癌细胞耐药性的出现,还参与了癌基因诱导的细胞衰老。和 IGFBP7) 参与响应 BRAF V600E 表达的细胞周期调节和癌基因诱导的衰老。因此,可以假设 SHP-2 不仅参与了癌细胞耐药性的出现,还参与了癌基因诱导的细胞衰老。和 IGFBP7) 参与响应 BRAF V600E 表达的细胞周期调节和癌基因诱导的衰老。因此,可以假设 SHP-2 不仅参与了癌细胞耐药性的出现,还参与了癌基因诱导的细胞衰老。
更新日期:2020-01-01
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