TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma
Authors: Yajin Chen
Xianqing Chen
Changzhen Shang
Wenliang Tan
Rui Zhou
Jun Cao
Jinyi Zhong
Xuan Luo
Sicong Zhu
Wenda Li
Journal: EBioMedicine (2019)
Discipline: CLINICAL MEDICINE
Keywords: Combination treatment; Hepatocellular carcinoma; Sorafenib resistance; TNF-α; Ulinastatin.
Affiliations: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China., Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Surgical Intensive Care Unit, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China., Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: .

Abstract:  Background: The role of tumor necrosis factor alpha (TNF-α) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-α to overcome sorafenib resistance in HCC. Methods: A correlation of TNF-α expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-α expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-α expression, on HCC were examined in vitro and in vivo. Findings: High TNF-α expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-α promotes HCC cell resistant to sorafenib through inducing epithelial-mesenchymal transition (EMT). Notably, the current study revealed that sorafenib has no significant influence on the expression and secretion of TNF-α, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-α expression. Inhibiting the expression of TNF-α with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-α in vitro and in vivo. Interpretation: Our findings indicate that TNF-α may serve as a novel predictor of sorafenib sensitivity in HCC patients. Sorafenib combined with ulinastatin may improve the effectiveness of treatment of HCC in patients with high expression of TNF-α. FUND: This work was supported by grants from the National Natural Science Foundation of China (no.81572398; no.81672419), the Science and Technology Planning Project of Guangdong Province (no. 2017A010105003; no.2015A050502023; no.2016A020216010), and the Natural Science Foundation of Guangdong Province (no.2014A030313061; no. 2013B021800101). 

Retracted: No

PubPeer comments:
 In fig4e, there was a overlap, and maybe more to expected in this paper. But I will stop for a while.![file] , 
 #1 Dear Dr. Passiflora Nephrodes, We do appreciate you for pointing out the error in our paper (in Fig.4e, there was an overlap between the invasion results of group u201ccontrolu201dand group u201cUTIu201d). We are sorry for the confusion to the readers. We double checked all the original data. After carefully checking the original data, we found this mistake happened during picture preparation. The image for group u201ccontrolu201d was mislabeled as the image for group u201cUTIu201d in Fig.4e (invasion assay), and the images for group u201csorafenibu201d and u201cUTIu201d were also mislabeled in Fig.4e (migration assay). These two errors have been corrected in the revised Fig.4e attached below. Since all the experiments have been repeated at least 3 times, this correction does not affect the conclusion of this article. We will apply for a correction to the EBioMedicine journal as soon as possible. We take full responsibility for this unintentional error and apologize to the editor, reviewers and readers for any inconvenience that caused by our mistake. Thank you very much for raising the concerns regarding the figures in our paper. Best regards! Tan Wenliang ![file] ,