Hepatocellular Carcinoma
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2021 ◽  
Vol 27 (40) ◽  
pp. 6737-6749
Adriana Ahumada ◽  
Laura Rayón ◽  
Clara Usón ◽  
Rafael Bañares ◽  
Sonia Alonso Lopez

2021 ◽  
Hong-Ming Yu ◽  
Kang Wang ◽  
Jin-Kai Feng ◽  
Lei Lu ◽  
Yu-Chen Qin ◽  

Abstract Background: Microvascular invasion (MVI) is a prominent risk factor of postoperative recurrence for hepatocellular carcinoma (HCC). The MVI detection rate of conventional pathological examination approaches is relatively low and unsatisfactory.Methods: By integrating pathological macro-slide with whole-mount slide imaging, we first created a novel pathological examination method called image-matching digital macro-slide (IDS). Surgical samples from eligible patients were collected to make IDS. The MVI detection rates, tumor recurrence rates and recurrence-free survival were compared among conventional 3-Point and 7-Point baseline sampling protocols and IDS. Additionally, biomarkers to recognize MVI false negative patients were probed via combining conventional pathological sampling protocols and IDS. Receiver operating characteristic curve (ROC) analysis was used to obtain the optimal cutoff of biomarkers to distinguish MVI false negative status.Results: The MVI detection rates were 21.98%, 32.97% and 63.74%, respectively, in 3-Point, 7-Point baseline sampling protocols and IDS (P< 0.001). Tumor recurrence rate of patients with MVI negative status in IDS (6.06%) was relatively lower than that of patients with MVI negative status in 3-Point (16.90%) and 7-Point (16.39%) sampling protocols. Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) was selected as potential biomarkers to distinguish MVI false negative patients.Conclusions: Our study demonstrated that IDS can help enhance the detection rate of MVI in HCC and refine the prediction of HCC prognosis. Alpha-fetoprotein is identified as a suitable and robust biomarker to recognize MVI false-negative patients in conventional pathological protocols.

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324170
Ningning Liu ◽  
Xiaomei Wang ◽  
Clifford John Steer ◽  
Guisheng Song

ObjectiveKupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood.DesignFVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system.ResultsHydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8+ T cells impaired the ability of miR-206 to prevent HCC.ConclusionsM2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8+ T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach.

2021 ◽  
Da-peng Sun ◽  
Xiao-jie Gan ◽  
Lei Liu ◽  
Yuan Yang ◽  
Dong-yang Ding ◽  

Abstract Background: DNA methylation plays a pivotal role in the development and progression of tumors, but studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. This manuscript is aimed to construct pre- and early DNA methylation maps of liver cancer of the same genetic background, as well as to reveal the mechanism of epigenetics regulating gene expression during the development of liver cancer, thus providing new targets and clinical evidence for early diagnosis and shedding lights on the precise treatment for liver cancer. Methods: The study includes 5 patients who were chronic hepatitis B virus infected, clinically diagnosed as primary liver cancer and pathologically diagnosed as early liver cancer with liver dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients have been used to measure DNA methylation. Results: We report significant differences in the DNA methylation spectrum of three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding of transcription factor P53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and disease-free survival of patients with high ZNF334 expression are longer than the lower one. Conclusions: We constructed a sequential map of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites, and also provide new targets and clinical evidence for the early diagnosis and precise treatment of liver cancer.

2021 ◽  
Kyunghan Lee ◽  
Gwang Hyeon Choi ◽  
Eun Sun Jang ◽  
Sook-Hyang Jeong ◽  
Jin–Wook Kim

Abstract Background & Aims: The role of hepatocellular carcinoma (HCC) surveillance is being questioned in alcoholic cirrhosis because of the relative low HCC risk. Comorbid viral hepatitis may synergistically increase the HCC risk in alcoholic cirrhosis. This study aimed to assess the risk and predictors of HCC in patients with alcoholic cirrhosis by using competing risk analysis in an area with intermediate prevalence for hepatitis B virus.Methods: A total of 965 patients with alcoholic cirrhosis were recruited at a university-affiliated hospital in Korea and randomly assigned to either the derivation (n=643) and validation (n=322) cohort. Subdistribution hazards model of Fine and Gray was used with deaths and liver transplantation treated as competing risks. Death records were confirmed from Korean government databases. A nomogram was developed to calculate the Alcohol-associated Liver Cancer Estimation (ALICE) score.Results: Markers for viral hepatitis were positive in 21.0 % and 25.8 % of patients in derivation and validation cohort, respectively. The cumulative incidence of HCC was 13.5 and 14.9 % at 10 years for derivation and validation cohort, respectively. Age, positivity for viral hepatitis markers, alpha-fetoprotein level, and platelet count were identified as independent predictors of HCC and incorporated in the ALICE score, which discriminated low, intermediate, and high risk for HCC in alcoholic cirrhosis at the cut-off of 120 and 180. Conclusions: HCC risk can be stratified by using clinical parameters including viral markers in alcoholic cirrhosis in an area where the prevalence of viral hepatitis is substantial.

2021 ◽  
Vi Thao Nguyen ◽  
Truc Thanh Nguyen ◽  
Hai Thanh Le ◽  
Hung Quoc Phan ◽  
Hien T. Pham

2021 ◽  
Vol 7 (1) ◽  
Xianlei Cai ◽  
Yunhao Chen ◽  
Da Man ◽  
Beng Yang ◽  
Xiaode Feng ◽  

AbstractThe function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1–YES1–MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.

2021 ◽  
Vol 11 ◽  
Linbin Lu ◽  
Peichan Zheng ◽  
Zhixian Wu ◽  
Xiong Chen

BackgroundThe selection criteria for hepatic resection (HR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) are still controversial. We used real-world data to evaluate the overall survival (OS) in treatment with HR or transarterial chemoembolization (TACE).MethodsIn total, 942 patients with IM-HCC were categorized into the HR group and the TACE group. OS was analyzed using the Kaplan–Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched (PSM) analysis. Curve smoothing was performed through the generalized additive model. The interaction test was performed to evaluate the impact of HR on OS concerning risk factors. Also, we used multiple imputation to deal with missing data.ResultsIn total, 23.0% (n = 225) of patients received HR. At a median OS of 23.7 months, HR was associated with improved OS in the multivariate analysis [hazard ratio (HzR) = 0.45, 95%CI = 0.35–0.58; after PSM: HzR = 0.56, 95%CI = 0.41–0.77]. Landmark analyses limited to long-term survivors of ≥6 months, ≥1 year, and ≥2 years demonstrated better OS with HR in all subsets (all p &lt; 0.05). After PSM analysis, however, HR increased the risk of death by 20% (HzR = 1.20, 95%CI = 0.67–2.15) in the subgroup of patients with lactate dehydrogenase (LDH) ≤192 U/L (p for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and HR with respect to the 1-, 3-, and 5-year observed survival rates (all p &lt; 0.05).ConclusionHR was superior to TACE for intermediate-stage HCC in patients with LDH levels &gt;192 U/L. Moreover, TACE might be suitable for patients with LDH levels ≤192 U/L.

2021 ◽  
Vol 11 ◽  
Junhua Li ◽  
Wei Zhou ◽  
Qiang Mao ◽  
Dandan Gao ◽  
Lin Xiong ◽  

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

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