Analyse des p53/HIF-1A/miR-34a Signalweges beim kolorektalen Karzinom
Zusammenfassung der Projektergebnisse
Tumor-associated hypoxia, i.e. decreased availability of oxygen, results in a poor clinical outcome since it promotes EMT, metastasis and chemotherapy-resistance. We have previously identified p53 and its target miR-34a, as critical determinants of the effect of hypoxia on colorectal cancer (CRC). Here, we aimed to characterize mechanisms that contribute to the selective advantage of cells with loss of p53/miR-34a function in a hypoxic environment. Using in silico prediction, we identified XBP-1 and IRE1A as potential miR-34a targets. IRE1A and XBP-1 are central components of the unfolded protein response that is activated by ER stress, which is also induced in tumor cells as response to harsh conditions surrounding tumors such as hypoxia and limited supply with nutrients. Here we characterized the XBP-1(S) transcription factor and its regulator IRE1A as direct, conserved miR-34a targets in CRC cells. After hypoxia and DNA damage, IRE1A and XBP1A were repressed by p53 in a miR- 34a-dependent manner, whereas p53-deficient cells showed induction of IRE1A and XBP-1(S). Furthermore, miR-34a expression was directly suppressed by XBP-1(S). In p53-deficient CRC cells hypoxia-induced EMT, migration, invasion, metastases formation and resistance to 5-FU was dependent on IRE1A/XBP-1(S) activation. Hypoxia-induced autophagy was identified as a XBP-1(S)- dependent mediator of 5-FU resistance and was reversed by ectopic miR-34a expression. The HIF1A/IRE1A/XBP-1(S)/p53/miR-34a feedback loop described here represents a central regulator of the response to hypoxia and ER stress that maintains cellular homeostasis. In tumors, the inactivation of p53 and miR-34a may result in IRE1A/XPB-1(S)-mediated EMT and autophagy, which ultimately promotes metastasis and chemoresistance.
Projektbezogene Publikationen (Auswahl)
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miR-34a and IRE1A/XBP-1(S) Form a Double-Negative Feedback Loop to Regulate Hypoxia-Induced EMT, Metastasis, Chemo-Resistance and Autophagy. Cancers, 15(4), 1143.
Bouznad, Nassim; Rokavec, Matjaz; Öner, Meryem Gülfem & Hermeking, Heiko
