Inhibitor of differentiation 1 contributes to head and neck squamous cell carcinoma survival via the NF-kappaB/survivin and phosphoinositide 3-kinase/Akt signaling pathways.
OBJECTIVE
A key issue in cancer is apoptosis resistance. However, little is known about the transcription factors that contribute to cellular survival of head and neck squamous cell carcinoma (HNSCC).


METHODS
Three batches (54, 64, and 38) of HNSCC specimens were used for cellular and molecular analyses to determine the major molecular signaling pathways for cellular survival in HNSCC. Animal models (cell culture and xenografts) were used to verify the importance of apoptosis resistance in HNSCC.


RESULTS
Inhibitor of differentiation (Id) family member, Id1, was significantly upregulated 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 3-kinase and increased the expression of survivin via NF-kappaB. Blockage of both pathways by specific inhibitors (LY294002 and IkappaBalphaM, respectively) abrogated Id1-induced cell survival of keratinocytes. In vivo studies showed that increased expression of Id1 allowed nontumorigenic 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 for Id1 significantly reduced HNSCC tumor volume 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.
Lin
Jizhen
J
Department of Otolaryngology, Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. linxx004@umn.edu
Guan
Zhong
Z
Wang
Chuan
C
Feng
Ling
L
Zheng
Yiqing
Y
Caicedo
Emiro
E
Bearth
Ellalane
E
Peng
Jie-Ren
JR
Gaffney
Patrick
P
Ondrey
Frank G
FG
D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation
C107489:BIRC5 protein, human; C497453:ID1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D051798:Inhibitor of Differentiation Protein 1; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D000077022:Survivin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt