Correlation Of Overexpression Of HMGA1 And HMGA2 With Poor Tumor Differentiation, Invasion, And Proliferation Associated With Let-7 Down-regulation In Retinoblastomas

In addition to RBI, the causative genes involved in the tumorigenesis and progression of retinoblastomas remain to be elucidated. High-mobility group Al 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=0.05 and P=0.0001, 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=0.01 and P=0.0001, respectively). High-mobility group A2 expression levels were significantly higher in invasive tumors than in noninvasive tumors (P=0.05). In addition, the MIB-1 labeling index was higher in poorly differentiated tumors than in well-differentiated tumors (P=0.0001). 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=0.029; R= 0.602, P=0.0001; 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=0.105). In addition, a significantly inverse association was detected between let-7 and highmobility group A2 and MIB-1 labeling index (r=-0.31, P= 0.04; r=-0.392, P=0.007, respectively). Our findings imply that the overexpressions of high-mobility group A1, high-mobility group A2, and downregulation of let-7 may be associated with tumorigenesis and progression of retinoblastomas.