title: Correlation of overexpression of HMGA1 and HMGA2 with poor tumor differentiation, invasion, and proliferation associated with let-7 down-regulation in retinoblastomas.
abstract: In addition to RB1, the causative genes involved in the tumorigenesis and progression of retinoblastomas remain to be elucidated. High-mobility group A1 and high-mobility group A2 proteins are expressed at high levels in various benign and malignant tumors and are associated with expressions of malignant phenotypes and poor prognoses. Reduction in let-7 expression levels was detected in cancers; it may be related to high-mobility group A1 and high-mobility group A2 overexpressions. Little is known about the correlations among high-mobility group A1, high-mobility group A2, and let-7 expression and clinicopathologic features of retinoblastoma. In our study, the expressions of high-mobility group A1 and high-mobility group A2 were studied in 44 retinoblastomas by immunohistochemical analysis. Semiquantitative reverse transcription-polymerase chain reaction was used to assay the let-7 expression levels in 28 nontumor retina and 44 tumor samples. Nuclear immunostaining of high-mobility group A1 and high-mobility group A2 was frequently observed in retinoblastomas (68% and 75%, respectively). Expression levels of both high-mobility group A1 and high-mobility group A2 were significantly higher in poorly differentiated retinoblastomas than in well-differentiated retinoblastomas (P < .05 and P < .0001, respectively). In addition, overexpressions of high-mobility group A1 and high-mobility group A2 were more frequently detected in poorly differentiated tumors than in well-differentiated tumors (P < .01 and P = .0001, respectively). High-mobility group A2 expression levels were significantly higher in invasive tumors than in noninvasive tumors (P < .05). In addition, the MIB-1 labeling index was higher in poorly differentiated tumors than in well-differentiated tumors (P < .0001). Our study revealed that high-mobility group A1 and high-mobility group A2 expressions correlated with the MIB-1 labeling index (R = 0.327, P = .029; R = 0.602, P < .0001; respectively). The let-7 was expressed in high levels in all 28 nontumor retina samples. However, reduced expression levels of let-7 were observed in 17 (39%) tumors. A potentially inverse correlation exists between the expression levels of let-7 and high-mobility group A1 (r = -0.247, P = .105). In addition, a significantly inverse association was detected between let-7 and high-mobility group A2 and MIB-1 labeling index (r = -0.31, P = .04; r = -0.392, P = .007, respectively). Our findings imply that the overexpressions of high-mobility group A1, high-mobility group A2, and down-regulation of let-7 may be associated with tumorigenesis and progression of retinoblastomas.
authors.affiliation: Department of Ophthalmology, Jinan Central Hospital affiliated to Shandong University, No. 105, Jiefang Road, Jinan 250013, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Mu
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Xu
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D005260:Female; D024003:HMGA Proteins / Q000096:biosynthesis*; D025743:HMGA2 Protein / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D012160:Retina / Q000378:metabolism; D019572:Retinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D012175:Retinoblastoma / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024003:HMGA Proteins; D025743:HMGA2 Protein; D019394:Ki-67 Antigen; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human