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首页> 外文期刊>Cellular Signalling >MMP-9 silencing regulates hTERT expression via β1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells
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MMP-9 silencing regulates hTERT expression via β1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells

机译：MMP-9沉默通过β1整合素介导的FAK信号传导调节hTERT表达并诱导胶质瘤异种移植细胞衰老

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摘要

In more than 90% of cancers including glioma, telomere elongation reverse transcriptase (hTERT) is overexpressed. In the present study, we sought to explore whether matrix metalloproteinase-9 (MMP-9) shRNA could alter hTERT-mediated proliferation in glioma cells. MMP-9 shRNA induced senescence and apoptosis in glioma cells by inhibiting hTERT expression and telomere activity. MMP-9 silencing decreased oncogenic c-Myc expression (hTERT activator), whereas the expression of the c-Myc antagonist MAD increased drastically (hTERT repressor); both c-Myc and MAD are transcription factors for hTERT. In addition, MMP-9 suppression turns the switch from c-Myc/MAX to MAD/MAX heterodimer binding to the hTERT promoter as determined by chromatin immunoprecipitation assay. We also show that silencing MAD via siRNA restored hTERT expression and inhibited senescence in glioma cells. MMP-9 transcriptional suppression decreased the expression of FAK, phospho FAK and β1 integrin in glioma xenograft cells. Further, MMP-9 suppression decreased the interaction of β1 integrin/FAK and also MMP-9/β1 integrin as confirmed by immunoprecipitation analysis. Studies with either function blocking β1 integrin or FAK shRNA indicate that suppression of MMP-9 decreased β1 integrin-mediated induction of FAK, which led to decreased hTERT expression. Moreover, 4910 and 5310 glioma xenograft tissue sections from mice treated with MMP-9 shRNA showed reduced expression of FAK/c-Myc and elevated MAD levels. Decreased co-localization of β1 integrin and MMP-9 was associated with MMP-9-suppressed tumor sections. Further, immunoprecipitation analysis showed decreased association of proteins involved in telomere end repair in MMP-9 shRNA-treated glioma cells. Elevated levels of p73 and TRAIL and the results of the FACS analysis show induction of apoptosis in MMP-9-silenced glioma cells. Taken together, these data provide new insights into the mechanisms underlying MMP-9-mediated hTERT expression in glioma proliferation.
机译：在包括神经胶质瘤在内的超过90％的癌症中，端粒伸长逆转录酶（hTERT）过度表达。在本研究中，我们试图探讨基质金属蛋白酶9（MMP-9）shRNA是否可以改变hTERT介导的胶质瘤细胞增殖。 MMP-9 shRNA通过抑制hTERT表达和端粒活性诱导神经胶质瘤细胞衰老和凋亡。 MMP-9沉默降低致癌性c-Myc表达（hTERT激活剂），而c-Myc拮抗剂MAD的表达则急剧增加（hTERT阻遏物）。 c-Myc和MAD都是hTERT的转录因子。此外，通过染色质免疫沉淀测定，MMP-9抑制作用将c-Myc / MAX切换为与hTERT启动子的MAD / MAX异二聚体结合。我们还显示，通过siRNA沉默MAD可恢复hTERT表达并抑制神经胶质瘤细胞的衰老。 MMP-9转录抑制可降低胶质瘤异种移植细胞中FAK，磷酸FAK和β1整合素的表达。此外，如通过免疫沉淀分析所证实的，MMP-9抑制降低了β1整联蛋白/ FAK以及MMP-9 /β1整联蛋白的相互作用。用功能阻断β1整合素或FAK shRNA进行的研究表明，抑制MMP-9可降低β1整合素介导的FAK诱导，从而导致hTERT表达降低。此外，用MMP-9 shRNA处理过的小鼠的4910和5310胶质瘤异种移植组织切片显示FAK / c-Myc的表达降低，MAD水平升高。 β1整合素和MMP-9的共定位降低与MMP-9抑制的肿瘤切片有关。此外，免疫沉淀分析显示参与MMP-9 shRNA处理的神经胶质瘤细胞中涉及端粒末端修复的蛋白质的缔合减少。 p73和TRAIL的水平升高以及FACS分析的结果表明，诱导MMP-9沉默的神经胶质瘤细胞凋亡。综上所述，这些数据为神经胶质瘤增殖中MMP-9介导的hTERT表达的潜在机制提供了新的见解。

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