In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3133-3133
Abstract:
Sorafenib is the promising first-line drug to treat advanced hepatocellular carcinoma (HCC), with the acquired resistance within 6 months in most treated patients. The epithelial-mesenchymal transition (EMT)-driven cancer metastasis contributes to sorafenib resistance via multiple signaling pathways, but the underlying molecular mechanism remains elusive. Recent studies showed that inflammatory cytokines TNF-α functionally initiates EMT through NF-κB mediated Snail activation in HCC, and that TRAF-interacting protein TIFA sustains the positive feedback loop between TNF-α and NF-κB that enhances chemoresistance in AML. Here we investigated the functional link between TIFA-regulated NF-κB inflammatory signaling and sorafenib resistance as a potential therapeutic target in the treatment of HCC. We showed that severe hepatitis induced in HCC mice promoted intrahepatic metastasis concurrently with NF-κB-driven EMT via Snail, and that HCC patients with hepatitis displayed poorer responses to sorafenib and unfavorable clinical outcome. In support, inflammatory TNF-α stimulation promoted levels of TIFA, NF-κB signaling factors, and EMT axis independent of sorafenib treatment, while silencing of TIFA or RelA perturbed sorafenib-dependent cytokine secretion in HCC cells. In addition, silencing of TIFA or RelA suppressed pro-survival factors Bcl-2 and Bcl-XL, and promoted pro-apoptotic factor BAX in response to sorafenib treatment in vitro. Consequently, HCC cells regained sorafenib chemosensitivity upon silencing of TIFA or RelA through promoted apoptosis. To further explore the therapeutic relevance, shRNAs were delivered using the liver-tropic adeno-associated virus serotype 8 in mice with orthotopic HCC xenografts, and results showed that targeting TIFA or RelA specifically enhanced sorafenib chemotoxicity resulting in more prominent tumor regression. Our results collectively showed that TIFA and NF-κB support inflammatory responses to offset sorafenib cytotoxicity, and that their targeting are therapeutically effective concomitant with sorafenib treatment in HCC. Citation Format: Tong-You Wade Wei, Pei-Yu Wu, Ting-Jung Wu, Ming-Daw Tsai. NF-κB-dependent inflammatory responses offset sorafenib cytotoxicity in hepatocellular carcinoma via TIFA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2017-3133
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-3133
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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