Purpose Oleanolic acid (OA) has been widely reported to possess antitumor effects, but the specific molecular mechanism underlying its inhibition of hepatocellular carcinoma (HCC) progression remains unclear. This study aims to uncover the mechanism of OA antitumor effect on HBV-associated HCC and identify a potential biomarker for tumor progression. Patients and Methods The effect of OA on major cellular processes of HBV-associated HCC cells was evaluated by CCK8 and Transwell assay. The potential molecular mechanism was assessed by cell transfection. This study also enrolled 111 HCC patients infected with HBV to evaluate the prognostic potential of lncRNA SNHG18 (SNHG18) in HBV-associated HCC. Results The inhibitory effect of OA was observed in the critical cellular processes of HBV-associated HCC cells, which depend on OA concentration. Downregulated SNHG18 in HBV-associated HCC was demonstrated to be involved in disease development and predict patients’ prognosis. The downregulation of SNHG18 dramatically promoted cellular processes of HBV-associated HCC could reverse the inhibitory effect of OA. Conclusion SNHG18 served as a tumor suppressor and prognostic biomarker of HBV-associated HCC. Enhancing SNHG18 might be the mechanism underlying the antitumor effect of OA in HBV-associated HCC.

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AbstractsImatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that thioredoxin-interacting protein (TXNIP) is a novel BCR-ABL target gene. Suppression of TXNIP was responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provided a novel survival pathway for the transformation of mouse bone marrow cells. Knockout of TXNIP accelerated BCR-ABL transformation, whereas TXNIP overexpression suppressed this transformation. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.