Trusting your gut-a new direction in multikinase inhibitors therapy in hepatocellular carcinoma

∼22 nucleotides.They play an important role in gene regulation and can exert tumor suppressive or oncogenic functions.p53 is known to regulate miRs in a range of cancer entities, but little is known about p63-and p73-dependent control of miRs in HCC.Aim of this study was to evaluate regulation of tumorsuppressive miRs by TAp63 and TA/DNp73 in HCC alone or in combination with HCC-relevant therapeutics.Method: Hep3B cells were transduced with adenoviral vectors rAd-TAp63, -TAp73, -DNp73 or -GFP to induce expression of the respective p53 family member.(Non-)transduced cells were stimulated with different HCC therapeutics (Doxorubicin, Bleomycin, Regorafenib, Sorafenib, Tivantinib) for up to 72 hours.Expression profiles of tumorsuppressive miRs miR-34a, -145, -149, -192 and -194 were analyzed by RT-qPCR.Results: Tivantinib induced an increase of all miRs analyzed in nontransduced Hep3B cells, with most effective induction of miR-34a and miR-145 (3.6×/7.4×),while other drugs had no effect.TAp63 transduction moderately increased miR-34a, -149, -192, and -194.TAp73 time-dependently induced miR-34a, -145 and -149, but had no effect on miR-192 and -194.Noteworthy, DNp73 did not induce any of the miRs, underlining the divergent functions of TA and DN isoforms.HCC therapeutics led to a moderate increase of all analyzed miRs in TAp63-transduced cells.In contrast, Tivantinib treatment highly increased (up to 15×) miR-34a, -145 and -149 in TAp73transduced cells, whereas all other drugs resulted in induction rates of 4-8×.Importantly, in TAp73-transduced cells this reinforcing effect of Tivantinib also displayed a dose-dependency.Conclusion: TAp63 and TAp73 regulate expression profiles of tumorsuppressive miRs and interact with HCC-relevant therapeutics to control miR expression profiles in HCC.In concordance with our previous data, DNp73 displayed divergent effects regarding miR regulation.Thus, specific combinations of p53 family members and HCC therapeutics-especially TAp73 and Tivantinib-have the capacity to reinforce tumorsuppressive miR expression.These findings provide novel knowledge to the complex network of p53 familymediated tumor suppression and suggest novel therapeutic scope for the clinical management of HCC.