A hMTR4‐PDIA3P1‐miR‐125/124‐TRAF6 Regulatory Axis and Its Function in NF kappa B Signaling and Chemoresistance

BACKGROUND AND AIMS: DNA damage‐induced NF‐κB activation is a major obstacle to effective antitumour chemotherapy. Long noncoding RNAs (lncRNAs) that regulate chemoresistance of cancer cells remain largely unknown. This study aimed to characterize the lncRNAs that may affect chemotherapy sensitivity. APPROACH AND RESULTS: We found that lncRNA PDIA3P1 (protein disulfide isomerase family A member 3 pseudogene 1) was up‐regulated in multiple cancer types and following treatment with DNA‐damaging chemotherapeutic agents, like doxorubicin (Dox). Higher PDIA3P1 level was associated with poorer recurrence‐free survival of human hepatocellular carcinoma (HCC). Both gain‐of‐function and loss‐of‐function studies revealed that PDIA3P1 protected cancer cells from Dox‐induced apoptosis and allowed tumor xenografts to grow faster and to be more resistant to Dox treatment. Mechanistically, miR‐125a/b and miR‐124 suppressed the expression of tumor necrosis factor receptor‐associated factor 6 (TRAF6), but PDIA3P1 bound to miR‐125a/b/miR‐124 and relieved their repression on TRAF6, leading to activation of the nuclear factor kappa B (NF‐κB) pathway. Consistently, the effect of PDIA3P1 inhibition in promoting Dox‐triggered apoptosis was antagonized by silencing the inhibitor of κBα (IκBα) or overexpressing TRAF6. Administration of BAY 11‐7085, an NF‐κB inhibitor attenuated PDIA3P1‐induced resistance to Dox treatment in mouse xenografts. Moreover, up‐regulation of PDIA3P1 was significantly correlated with elevation of TRAF6, phosphorylated p65, or NF‐κB downstream anti‐apoptosis genes in human HCC tissues. These data indicate that enhanced PDIA3P1 expression may confer chemoresistance by acting as a microRNA sponge to increase TRAF6 expression and augment NF‐κB signaling. Subsequent investigations into the mechanisms of PDIA3P1 up‐regulation revealed that human homologue of mRNA transport mutant 4 (hMTR4), which promotes RNA degradation, could bind to PDIA3P1, and this interaction was disrupted by Dox treatment. Overexpression of hMTR4 attenuated Dox‐induced elevation of PDIA3P1, whereas silencing hMTR4 increased PDIA3P1 level, suggesting that Dox may up‐regulate PDIA3P1 by abrogating the hMTR4‐mediated PDIA3P1 degradation. CONCLUSION: There exists a hMTR4‐PDIA3P1‐miR‐125/124‐TRAF6 regulatory axis that regulates NF‐κB signaling and chemoresistance, which may be exploited for anticancer therapy.