Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells.
The oncogenic potential of Notch activation is observed in many instances including lung tumorigenesis, but the associated molecular regulatory mechanism has not been thoroughly defined. It has been demonstrated that hypoxia can act as one of the major stimuli in the progression of many types of tumorigenesis. This study was designed to examine the activation of Notch-1 signaling by hypoxia and its contribution to survivin expression in human lung carcinomas. Western-blot and PCR analysis showed that Notch-1 signaling is activated by hypoxia in the human non-small cell lung cancer (NSCLC) cell line, A549, through the upregulation of Notch-1, along with its intracellular domain (N1ICD). The activity of Hes-1, a crucial target molecule of N1ICD, was also increased under hypoxia. Interestingly, blockade of the Notch-1 pathway by a γ-secretase inhibitor or small interfering RNA (siRNA) inhibited survivin expression. Conversely, activation of Notch-1 signaling by N1ICD or stimulation with the Jagged1 ligand enhanced survivin levels in A549 cells. Notably, HIF-1α cooperated with Notch-1 signaling to increase survivin expression through its direct association with N1ICD, consequently accelerating survivin transcription. Overall, our findings suggest that Notch-1 signaling is involved in the upregulation of survivin expression in lung cancer cells, which is synergized by HIF-1α.
Chen
Yuqing
Y
Department of Respiration, First Affiliated Hospital Bengbu Medical College, Bengbu, Anhui, China.
Li
Dianming
D
Liu
Hongli
H
Xu
Huanbai
H
Zheng
Honghua
H
Qian
Feng
F
Li
Wei
W
Zhao
Chengling
C
Wang
Zhenhuan
Z
Wang
Xiaojing
X
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000077022:Survivin; D000072056:Transcription Factor HES-1; D014162:Transfection; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000077022:Survivin; D000072056:Transcription Factor HES-1; C107489:BIRC5 protein, human; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; C497761:NOTCH1 protein, human; C078493:HES1 protein, human