title: Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer.
abstract: TheCullin-RING ubiquitinligase 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair, and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B, are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human patients with cancer. In our study, 352 lung cancer and 62 normal lung specimens of Asian origin were constructed into tissue microarrays of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B, and their substrates was detected by immunohistochemistry and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Our results show that both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A<0.001 andPCUL4B<0.001) and significantly associated with tumor size (PCUL4A<0.001 andPCUL4B= 0.002), lymphatic invasion (PCUL4A= 0.004 andPCUL4B<0.001), metastasis (PCUL4A= 0.019 andPCUL4B= 0.006), and advanced TNM stage (PCUL4A<0.001 andPCUL4B<0.001), which parallels gene amplification and abnormal activation of the canonical WNT signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (p= 0.01) and is inversely correlated with XPC and P21, both of which are substrates of CUL4A (PCUL4A= 0.019 andPCUL4B= 0.006). Higher levels of CUL4A or CUL4B are significantly associated with the overall survival of patients (PCUL4A<0.001 andPCUL4B<0.001) and progression-free survival (PCUL4A<0.001 andPCUL4B= 0.001). Our findings revealed that CUL4A and CUL4B are differentially associated with etiologic factors for pulmonary malignancies and are independent prognostic markers for the survival of distinct lung cancer subtypes.
authors.affiliation: From the Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy.
authors.forename: Lei
authors.initials: L
authors.lastname: Jia
authors.affiliation: From the Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy.|the Departments of Pathology and Laboratory Medicine and.
authors.forename: Fan
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Pathology, Key Laboratory of Tianjin Cancer Prevention and Treatment.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cao
authors.affiliation: Healthcare Policy and Research, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, and.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology and Biostatistics, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, and.
authors.forename: Haixin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Key Laboratory of Tianjin Cancer Prevention and Treatment.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: the Departments of Pathology and Laboratory Medicine and.
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.affiliation: From the Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, rwziyi@yahoo.com.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: From the Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, lihui@tjmuch.com.|the Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China and.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, pez2001@med.cornell.edu.|the Departments of Pathology and Laboratory Medicine and.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
mesh_terms: D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000145:classification / Q000201:enzymology* / Q000473:pathology; D011379:Prognosis; D012907:Smoking; D013379:Substrate Specificity; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D053722:Receptors, Interleukin-17
chemical_list: D044842:Cullin Proteins; D044767:Ubiquitin-Protein Ligases; C517832:CUL4B protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17
keywords: E3 ubiquitin ligase; cell signaling; immunohistochemistry; lung cancer; protein degradation; ubiquitin; ubiquitin ligase