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.