Abstract
AbstractI have previously proposed that TA-p73-depenedent tumor suppressor pathway could inhibit the development of lung adenocarcinoma. This hypothesis is strongly supported by a recent finding showing that TA-p73 specific knockout mice are prone to lung adenocarcinoma. However, the p73-dependent tumor suppressor pathway remains ill defined. It has been shown that let-7 cluster is highly expressed in normal lung. Loss of let-7 expression: a) is common in Non-small cell lung carcinoma; and b) enhances lung tumor formation, indicating that it could function as a lung tumor suppressor. Based on these facts, I hypothesized that let-7 could be a transcriptional target of p73. To confirm this hypothesis, I have analyzed the let-7 cluster promoters using TRASFAC bioinformatics software. This analysis suggests that Let-7c contains three perfect p53-RE half-sites and five nearly perfect p53RE sites. In addition, other let-7 cluster miRNAs appear to contain several p53-REs, suggesting that Let-7 miRNA cluster could be a transcriptional target of p73/p63/p53. Furthermore, negative regulators of let-7 biogenesis, such as lin-28, c-myc and DCAMKL-1, are suppressed by p53-miRs, such as let-7, miR-145, miR-34, miR-15/16, miR-103/107 and miR-221, suggesting that TA-p73/p63/p53, by suppressing the expression of lin-28, c-myc and DCAMKL-1, it could increase the expression of let-7. By increasing the expression of let-7, TA-p73 could suppress the expression of its targets, such as N/H/K-ras, HMGA2, Cyclins, MCMs, BUBs, and CDCs; thereby it could inhibit the initiation of lung tumors. Together, this study proposes for the first time the TA-p73/p63-let-7-INK4a/ARF as a lung tumor suppressor pathway.
Highlights
I have previously proposed that E2F-1-TA-p73depenedent tumor suppressor pathway could inhibit the development of lung adenocarcinoma
This hypothesis is strongly supported by a recent finding showing that TA-p73 specific knockout mice are prone to lung adenocarcinoma
Loss of let-7 expression: a) is common in Non-small cell lung carcinoma; and b) enhances lung tumor formation, indicating that it could function as a lung tumor suppressor
Summary
I have previously proposed that E2F-1-TA-p73depenedent tumor suppressor pathway could inhibit the development of lung adenocarcinoma.This hypothesis is strongly supported by a recent finding showing that TA-p73 specific knockout mice are prone to lung adenocarcinoma. The TA-p73 functions as a Lung tumor suppressor by increasing the expression of miRNA, Let-7 Dr L.Boominathan Ph.D. M.Sc.,(Med. Bio., JIPMER), M.Sc., (Life Sci.,(Cancer bio.) Weizmann Inst., Israel), Ph.D.
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