Enhanced IMP3 Expression Activates NF-кB Pathway and Promotes Renal Cell Carcinoma Progression.
BACKGROUND
Insulin-like growth factor 2 mRNA binding protein 3 (IMP3) is expressed in metastatic and a subset of primary renal cell carcinoma (RCC). However, the role of IMP3 in RCC progression was poorly understood. We aim to uncover the mechanism of IMP3 in regulating clear cell RCC (CCRCC) progression and validate the prognostic significance of IMP3 in localized CCRCC.


METHODS
Caki-1 cells stably overexpressing IMP3 and Achn cells with knockdown of IMP3 were analyzed for cell migration and invasion by Transwell assay. RNA-seq was used to profile gene expression in IMP3-expressing Caki-1 cells. A cohort of 469 localized CCRCC patients were examined for IMP3 expression by immunohistochemistry using tumor tissue array.


RESULTS
IMP3 promoted Caki-1 cell migration and invasion, whereas knockdown of IMP3 by RNAi inhibited Achn cell migration and invasion. Enhanced IMP3 expression activated NF-кB pathway and through which, it functioned in promoting the RCC cell migration. IMP3 expression in localized CCRCC was found to be associated with higher nuclear grade, higher T stage, necrosis and sarcomatoid differentiation (p< 0.001). Enhanced IMP3 expression was correlated with shorter recurrence-free and overall survivals. Multivariable analysis validated IMP3 as an independent prognostic factor for localized CCRCC patients.


CONCLUSIONS
IMP3 promotes RCC cell migration and invasion by activation of NF-кB pathway. IMP3 is validated to be an independent prognostic marker for localized CCRCC.
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China; Department of Histology and Embryology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi, Xinjiang, PR China.
Xuelian
X
Pei
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Pathology, Peking University Health Science Center, Beijing, PR China.
Muhan
M
Li
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China.
Jun
J
Zhan
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China.
Yu
Y
Yu
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China.
Xiaofan
X
Wei
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China.
Lizhao
L
Guan
Institute of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio, United States of America.
Hakan
H
Aydin
Department of Quantitative Health Sciences, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio, United States of America.
Paul
P
Elson
Institute of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio, United States of America.
Ming
M
Zhou
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Pathology, Peking University Health Science Center, Beijing, PR China.
Huiying
H
He
Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, PR China; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, PR China.
Hongquan
H
Zhang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
D014408:Biomarkers, Tumor; C498780:IGF2BP3 protein, human; D016328:NF-kappa B; D016601:RNA-Binding Proteins