HMGA2等癌基因3’端非编码区的异常选择性剪接与其逃避microRNA抑制的关联和机制研究

Aberrant genetic alteration can activate oncogenes, thereby contributing to tumorigenesis. However, the elevated expression of the oncoproteins did not necessarily come with the increased gene transcription. Our pilot studies revealed that multiple lines of breast cancer cells often expressed substantial amounts of HMGA2 mRNA isoforms with shorter 3' untranslated regions (3'UTRs)compared with the normal breast cells. These shorter isoforms were presumably resulted from alternative splcing. The HMGA2 mRNA with shorter 3'UTR was more stable compared with the HMGA2 mRNA with longer 3'UTR, partially due to the loss of miRNA-mediated repression. This shortening of the 3'UTR results in the loss of the binding site for the suppressive miRNA and thus renders the mRNA with shorter 3'UTR less susceptible to miRNA-mediated suppression. These results implicate the importance of alternative splicing of mRNA 3'UTR in post-transcriptional control of oncogene expression.Further illustration of functional roles and mechanism of the shortening of oncogene mRNA in breast cancer developement will be addressed.

遗传学改变导致的癌基因的异常表达与激活是肿瘤发生发展的重要原因，然而癌基因在蛋白水平的过表达往往并不伴随着转录的上调。我们发现相对于正常细胞系，肿瘤细胞系中HMGA2等基因常表达大量3'端非编码区缩短的mRNA。这种缩短的mRNA的产生是由于其3'端非编码区发生了异常的选择性剪接。这种包含缩短3'端非编码区的短mRNA比长mRNA具有更高的稳定性，可能机制之一是由于其3'端非编码区的缩短造成某些miRNA与其结合位点的丢失；从而直接导致靶基因对相关miRNA所介导抑制性作用低敏感。这些结果表明mRNA 3'端非编码区的选择性剪接与相关miRNA组成的分子调控网络对于癌基因的转录后调控十分重要。在此基础上我们将通过生物信息学和一系列体外体内实验以及临床样本检测深入探讨HMGA2等癌基因3'端非编码区的异常选择性剪接与相关miRNA组成的分子调控网络在肿瘤发生发展中的功能特性和分子机制。

遗传学改变导致的癌基因的异常表达与激活是肿瘤发生发展的重要原因，然而癌基因在蛋白水平的过表达往往并不伴随着转录的上调。我们发现相对于正常细胞系，肿瘤细胞系中原癌基因常表达大量3’端非编码区缩短的mRNA。这种缩短的mRNA的产生是由于其3’端非编码区发生了异常的选择性多聚腺苷酸化（APA）。这种包含缩短3’端非编码区的短mRNA比长mRNA具有更高的稳定性，可能机制之一是由于其3’端非编码区的缩短造成某些miRNA与其结合位点的丢失；从而直接导致靶基因对相关miRNA所介导抑制性作用低敏感。这些结果表明mRNA 3’端非编码区的选择性剪接与相关miRNA组成的分子调控网络对于癌基因的转录后调控十分重要。在此基础上我们将通过生物信息学和一系列体外体内实验以及临床样本检测深入探讨癌基因3’端非编码区的异常选择性多聚腺苷酸化与相关miRNA组成的分子调控网络在肿瘤发生发展中的功能特性和分子机制。