Characterization of a novel mechanism of genomic instability involving the SEI1/SET/NM23H1 pathway in esophageal cancers.
Amplification of 19q is a frequent genetic alteration in many solid tumors, and SEI1 is a candidate oncogene within the amplified region. Our previous study found that the oncogenic function of SEI1 was associated with chromosome instability. In this study, we report a novel mechanism of genomic instability involving the SEI1-SET-NM23H1 pathway. Overexpression of SEI1 was observed in 57 of 100 of esophageal squamous cell carcinoma cases. Functional study showed that SEI1 had strong tumorigenic ability, and overexpression of SEI1 could induce the genomic instability by increasing micronuclei formation and reducing the number of chromosomes. Further study found that SEI1 was able to upregulate SET expression and subsequently promote the translocation of a small amount of NM23H1 from the cytoplasm to the nucleus. Nuclear NM23H1 can induce DNA damage through its DNA nick activity. Unlike CTL attack, only a small amount of NM23H1 translocated into the nucleus (<10%) induced by the overexpression of SEI1. Further study found that the small amount of NM23H1 only induced minor DNA damage and subsequently increased genomic instability, rather than inducing irreparable DNA damage and initiating apoptosis by CTL attack. Sister chromatid exchange experiment found that the translocation of small amount of NM23H1 into the nucleus induced by the overexpressions of SEI1/SET could increase the frequency of sister chromatid exchange. In addition, overexpression of SEI1 was associated with poor prognosis of esophageal squamous cell carcinoma. Taken together, these findings define a novel mechanism of genomic instability and malignant progression in esophageal cancers, a deadly disease of increasing incidence in developed countries.
Li
Yan
Y
State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Nie
Chang-Jun
CJ
Hu
Liang
L
Qin
Yanru
Y
Liu
Hai-Bo
HB
Zeng
Ting-Ting
TT
Chen
Leilei
L
Fu
Li
L
Deng
Wen
W
Chen
Shu-Peng
SP
Jia
Wei-Hua
WH
Zhang
Chunyu
C
Xie
Dan
D
Guan
Xin-Yuan
XY
D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction; D012854:Sister Chromatid Exchange; D014162:Transfection; D015854:Up-Regulation
D054778:NM23 Nucleoside Diphosphate Kinases; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human; C517938:NME1 protein, human