ΔNp63 versatilely regulates a Broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation.
ΔNp63 versatilely regulates a Broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation.
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DOI：
10.1158/0008-5472.can-10-3445
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Yang X;Lu H;Yan B;Romano RA;Bian Y;Friedman J;Duggal P;Allen C;Chuang R;Ehsanian R;Si H;Sinha S;Van Waes C;Chen Z
头颈部鳞状细胞癌（HNSCC）和许多上皮性恶性肿瘤表现出增殖、侵袭和炎症增加，并伴有TP53和NF-κB家族成员ΔNp63、c-REL和RELA的异常核激活。然而，这些转录因子协调基因表达和恶性表型的串扰机制仍然难以捉摸。在这里，我们证明thatΔNp63调节了一系列参与细胞生长、存活、粘附和炎症的基因，这些基因与NF-κB转录组有很大的重叠。含有c-REL和/或RELA的ΔNp63在多个靶基因启动子的p63或NF-κB/REL位点上形成新的结合复合物。过表达ΔNp63-或TNF-α-诱导的NF-κ b和炎症细胞因子IL-8报告因子的激活依赖于RELA/c-REL调节结合位点。通过siRNA耗尽RELA或ΔNp63可显著抑制NF-κ b特异性或TNF-α-诱导的IL-8报告因子激活。ΔNp63 siRNA在体外显著抑制HNSCC细胞的增殖、存活和迁移。与上述一致的是，与非恶性粘膜的基底区蛋白表达模式和最小炎症相比，整个HNSCC标本中观察到细胞核ΔNp63增加，同时伴有增殖（Ki67）和粘附（β4整合素）标志物的增加，以及诱导的炎症细胞浸润。此外，ΔNp63α在转基因小鼠鳞状上皮中的过表达导致基底上c-REL、Ki-67和细胞因子表达增加，并伴有表皮增生和弥漫性炎症，类似于HNSCC。我们的研究表明ΔNp63是一个主转录因子，与NF-κB/RELs协同，协调一个广泛的基因程序，促进表皮增生、炎症和HNSCC的恶性表型。
Head and neck squamous cell carcinoma (HNSCC) and many epithelial malignancies exhibit increased proliferation, invasion and inflammation, concomitant with aberrant nuclear activation of TP53 and NF-κB family members ΔNp63, c-REL and RELA. However, the mechanisms of crosstalk by which these transcription factors coordinate gene expression and the malignant phenotype remain elusive. Here we demonstrate thatΔNp63 regulates a cohort of genes involved in cell growth, survival, adhesion and inflammation, which substantially overlaps with the NF-κB transcriptome. ΔNp63 with c-REL and/or RELA are recruited to form novel binding complexes on p63 or NF-κB/REL sites of multiple target gene promoters. Overexpressed ΔNp63- or TNF-α-induced NF-κB and inflammatory cytokine IL-8 reporter activation depended upon RELA/c-REL regulatory binding sites. Depletion of RELA or ΔNp63 by siRNA significantly inhibited NF-κB-specific, or TNF-α-induced IL-8 reporter activation. ΔNp63 siRNA significantly inhibited proliferation, survival, and migration by HNSCC cells in vitro. Consistent with the above, an increase in nuclear ΔNp63 accompanied by increased proliferation (Ki67), and adhesion (β4 integrin) markers, and induced inflammatory cell infiltration was observed throughout HNSCC specimens, when compared to the basilar pattern of protein expression and minimal inflammation seen in non-malignant mucosa. Further, overexpression of ΔNp63α in squamous epithelia in transgenic mice leads to increased suprabasilar c-REL, Ki-67, and cytokine expression, together with epidermal hyperplasia and diffuse inflammation, similar to HNSCC. Our study reveals ΔNp63 as a master transcription factor that in coordination with NF-κB/RELs, orchestrates a broad gene program promoting epidermal hyperplasia, inflammation, and the malignant phenotype of HNSCC.