Inhibitor of Differentiation 1 Contributes to Head and Neck Squamous Cell Carcinoma Survival via the NF-κB/Survivin and Phosphoinositide 3-Kinase/Akt Signaling Pathways

Abstract

Purpose A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors which contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC). Experimental design Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses in order to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were employed to verify the importance of apoptosis resistance in HNSCC. Results Inhibitor of differentiation (Id) family member, Id1, was significantly up-regulated in clinical HNSCC specimens and acted to protect keratinocytes from apoptosis. Transfection of HNSCC cells with Id1 in vitro induced the phosphorylation of Akt (p-Akt) via phosphoinositide kinase-3 (PI3K) and increased the expression of survivin via nuclear factor kappa B (NF-κB). Blockage of the both pathways by specific inhibitors (LY294002 and IκBαM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies demonstrated that increased expression of Id1 allowed non-tumorigenic keratinocytes (Rhek-1A) to become tumorigenic in nude mice by increased expression of survival genes such as p-Akt and survivin. More importantly, short interfering RNA (siRNA) for Id1 significantly reduced HNSCC tumorvolume of HNSCC in xenograft studies. Analysis of clinical data verified the importance of the Id1 downstream molecule, survivin, in the prognosis of HNSCC patients. Conclusions The above data, taken together, suggest that Id1 and its downstream effectors are potential targets for treatment of HNSCC because of their contribution to apoptosis resistance.

Gene expression profile analysis of SUDHL6 cells with siRNA‐mediated BCL11A downregulation

“…Activated Akt can phosphorylate GSK3b (Lin et al, 2010). Expressions of several protein kinases, including the MAP2K6, MAP3K5, PPP3CA, MAP3K2, and MAP4K4, were deregulated in our study.…”

Cellular and molecular mechanisms of renal fibrosis

“…54 Expression of inhibitor of differentiation 1 (Id1), a dominant-negative transcriptional antagonist, is rapidly and markedly induced in the degenerated kidney tubules after obstructive injury. 55 Although Id1 represses the transcription of E-cadherin and tight junction protein ZO-1, leading to the dedifferentiation of tubular epithelial cells, 55 it also augments NFκB signaling 56,57 and potentiates the expression of CCL5 (also known as RANTES) in tubular cells. The notion that a single molecule such as Id1 promotes both epithelial dedifferentiation and chemokine expression in the same cells illustrates that inflammation and fibrosis are somehow intrinsically connected at the molecular level.…”

Regulation of the Angiogenesis of Acquired Middle Ear Cholesteatomas by Inhibitor of DNA Binding Transcription Factor

“…30 In the literature, VEGF has been shown to be linked to COX-2, which contributes to angiogenesis via prostaglandins. 31 Because Id1 induces the activity of the PI3K/Akt signaling pathway in keratinocytes, 32 we believe that Id1 regulates the angiogenesis via multiple signaling pathways (Figure 4).…”