Long-term persistent infection of HPV 16 E6 up-regulate SP1 and hTERT by inhibiting LKB1 in lung cancer cells.
Long-term persistent infection of HPV 16 E6 up-regulate SP1 and hTERT by inhibiting LKB1 in lung cancer cells.
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HPV 16 E6长期持续感染通过抑制肺癌细胞中的LKB1上调SP1和hTERT
DOI：
10.1371/journal.pone.0182775
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wu GP
中科院分区：
文献类型：
--
作者：
Yang JH;Li XY;Wang X;Hou WJ;Qiu XS;Wang EH;Wu GP
HPV 16 E6上调肺癌细胞hTERT表达然而，潜在的分子机制尚不清楚。采用qRT-PCR方法检测106例肺癌患者和68例肺良性疾病患者刷拭细胞中E6、LKB 1、SP1和hTERTmRNA的表达水平。恶性组E6、SP1和hTERT mRNA表达水平均高于良性组（P < 0.01）。恶性组LKB 1 mRNA表达水平明显低于正常组（P < 0.01）。E6、Sp1、hTERT与LKB 1之间存在相关性，E6、Sp1、hTERT之间呈正相关，LKB 1之间呈负相关（P < 0.01）。为了研究这些基因之间的潜在关系，我们使用双向遗传操作，我们发现在H1299细胞中E6过表达下调LKB 1 mRNA和蛋白表达，但上调SP 1和hTERT以及SP 1的转录活性。与此相反，在A549细胞中，通过短干扰RNA（siRNA）敲低E6上调LKB 1表达，但下调SP 1和hTERT表达以及SP 1活性。LKB 1缺失在蛋白和mRNA水平上上调SP1和hTERT以及SP1活性。为了验证E6对hTERT的作用是由SP1介导的，在H1299和A549细胞系上进行SP1的siRNA敲低。抑制SP1下调hTERT表达。结果表明，HPV 16 E6通过抑制LBK 1表达和上调Sp1表达间接上调hTERT表达，提示HPV-LKB 1-SP1-hTERT轴在肺癌的发生中起重要作用。我们的研究也为支持SP1和LKB 1在HPV相关肺癌发病机制中的关键作用提供了新的证据，并提出了新的治疗靶点。
HPV 16 E6 upregulates hTERT expression in lung cancer cells. However, the underlying molecular mechanism is unclear. In this paper, E6, LKB1, SP1, and hTERT mRNA expression levels were detected in brushing cells of patients with lung cancer (n = 106) and with benign lung disease (n = 68) by qRT-PCR. The mRNA expression levels of E6, SP1, and hTERT were significantly increased in the malignant group compared with the benign group (P < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (P < 0.01). Furthermore, the correlation between E6, Sp1, hTERT, and LKB1 was performed, our results indicated that E6, Sp1, and hTERT with positive, but LKB1 with negative correlation (P < 0.01). To investigate the potential relationship between these genes, using double directional genetic manipulation, we showed that overexpression of E6 in H1299 cells down-regulated LKB1 mRNA and protein expression but up-regulated SP1 and hTERT as well as the transcriptional activity of Sp1. In contrast, knockdown of E6 in A549 cells by short-interference RNAs (siRNAs) up-regulated LKB1 expression, but down-regulated SP1 and hTERT expression as well as Sp1 activity. LKB1 loss upregulated both SP1 and hTERT at the protein and mRNA level as well as SP1 activity. To verify that the role of E6 on hTERT was mediated by SP1, siRNA knockdown of SP1 was performed on both H1299 and A549 cell lines. Inhibition of SP1 downregulated hTERT expression. Our results indicate that HPV16 E6 indirectly upregulated the expression of hTERT by inhibition of LBK1 expression and upregulation of Sp1 expression, thus suggesting a HPV-LKB1-SP1-hTERT axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of SP1 and LKB1 in the pathogenesis of HPV-related lung cancer, and suggests novel therapeutic targets.
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