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NRF2 Dysregulation in Hepatocellular Carcinoma and Ischemia: A Cohort Study and Laboratory Investigation.
Ziv, Etay; Zhang, Yiru; Kelly, Luke; Nikolovski, Ines; Boas, F Edward; Erinjeri, Joseph P; Cai, Liqun; Petre, Elena N; Brody, Lynn A; Covey, Anne M; Getrajdman, George; Harding, James J; Sofocleous, Constantinos; Abou-Alfa, Ghassan K; Solomon, Stephen B; Brown, Karen T; Yarmohammadi, Hooman.
Afiliación
  • Ziv E; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Zhang Y; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Kelly L; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Nikolovski I; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Boas FE; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Erinjeri JP; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Cai L; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Petre EN; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Brody LA; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Covey AM; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Getrajdman G; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Harding JJ; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Sofocleous C; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Abou-Alfa GK; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Solomon SB; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Brown KT; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
  • Yarmohammadi H; From the Department of Radiology (E.Z., L.K., I.N., F.E.B., J.P.E., L.C., E.N.P., L.A.B., A.M.C., G.G., C.S., S.B.S., H.Y.), Sloan Kettering Institute (Y.Z.), and Department of Medicine (J.J.H., G.K.A.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; Department of Radiolo
Radiology ; 297(1): 225-234, 2020 10.
Article en En | MEDLINE | ID: mdl-32780006
Background Intermediate stage hepatocellular carcinomas (HCCs) are treated by inducing ischemic cell death with transarterial embolization (TAE) or transarterial chemoembolization (TACE). A subset of HCCs harbor nuclear factor E2-related factor 2 (NRF2), a major regulator of the oxidative stress response implicated in cell survival after ischemia. NRF2-mutated HCC response to TAE and/or TACE is unknown. Purpose To test whether ischemia resistance is present in individuals with NRF2-mutated HCC and if this resistance can be overcome by means of NRF2 inhibition in HCC cell lines. Materials and Methods This was a combined retrospective review of an institutional database (from January 2011 to December 2018) and prospective study (from January 2014 to December 2018) of participants with HCC who underwent TAE and a laboratory investigation of HCC cell lines. Imaging follow-up included liver CT or MRI at 1 month after the procedure followed by 3-month interval scans. Tumor radiologic response was assessed on the basis of follow-up imaging. The time to local progression after TAE for individuals with and individuals without NRF2 pathway alterations was estimated by using competing risk analysis (Gray test). The in vitro response to ischemia in four HCC cell lines with and without NRF2 overexpression was evaluated, and the combination of ischemia with NRF2 knockdown by means of short hairpin RNA or an NRF2 inhibitor was tested. Doubling time estimates, dose response curve regression, and comparison analyses were performed. Results Sixty-five individuals (median age, 69 years [range, 19-84 years]; 53 men) were evaluated. HCCs with NRF2 pathway mutation had a shorter time to local progression after TAE compared to those without mutation (6-month cumulative incidence of local progression, 56% [range, 19%-91%] vs 22% [range, 12%-34%], respectively; P < .001) and confirmed ischemia resistance in NRF2-overexpressing HCC cell lines. However, ischemia and NRF2 knock-down worked synergistically to decrease proliferation of NRF2-overexpressing HCC cell lines. Dose response curves of ML385, an NRF2 inhibitor, showed that ischemia induces addiction to NRF2 in cells with NRF2 alterations. Conclusion Hepatocellular carcinoma with nuclear factor E2-related factor 2 (NRF2) alterations showed resistance to ischemia, but ischemia simultaneously induced sensitivity to NRF2 inhibition. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Weiss and Nezami in this issue.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Factor 2 Relacionado con NF-E2 / Neoplasias Hepáticas Tipo de estudio: Etiology_studies / Observational_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Radiology Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Factor 2 Relacionado con NF-E2 / Neoplasias Hepáticas Tipo de estudio: Etiology_studies / Observational_studies / Risk_factors_studies Límite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Radiology Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos