Abstract
We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.
Highlights
We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression
The regulation of parental gene relies on several mechanisms: (i) the generation of endogenous short interfering RNAs2,3; (ii) the engagement of regulatory proteins on the parental gene by pseudogene RNAs to control gene expression and chromatin remodelling[4,5]; (iii) the ability of the pseudogenes to compete with the parental genes for RNA-binding proteins and the translation machinery[6,7,8]; (iiii) the ability of pseudogenes to compete with their parental genes for a common pool of shared microRNAs9 through the high sequence homology of the 3′ Untranslated region (UTR), regulating each other expression as competitive endogenous RNAs10
The expression of the HMGA1P7 was assessed in lungs, spleens and kidneys explanted from transgenic mice (Fig. 1)
Summary
We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues These results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo. They have no transcriptional activity per se, but, modifying the chromatin architecture, they are able to positively or negatively regulate the expression of several genes, those involved in cancer progression[11,12] These proteins are expressed at very low levels in normal adult tissues, but are abundant in almost all the human malignant neoplasms[11], and their expression significantly correlates with the capability of cancer cells to metastatize and a patient poor prognosis[13,14,15]. These results validate the oncogenic role of the HMGA1 pseudogenes[18]
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