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Background/Aims: ATP-binding cassette (ABC) transporters have been shown to regulate tumor initiating cells in various cancer types and specific genotype associated with cancer risk. ABCF1 was on priority among the ABC transporters because the gene located at 6p21, the chromosome region associated with a number of HCC risk genetic loci including the HLA genes. Its family member ABCF2 was also examined as their expression levels were highly correlated and associated with HCC recurrence. Subjects and Methods: A total of 300 HCC and 300 healthy blood samples (99.3% and 94.7% Chinese respectively) were prospectively collected with informed consent. All patients had been diagnosed with primary HCC and underwent partial hepatectomy. Clinical information including sex, age, tumor stage and survival outcomes were collected prospectively. Genomic DNA were extracted from blood samples and SNPs were examined by TaqMan genotyping assay, Sequenom MassARRAY platform and direct sequencing. Results: Sixteen SNPs and three INDELs were examined in ABCF1 and ABCF2 in the germline DNA of 300 HCCs and 300 healthy individuals. Among the 19 loci investigated, ABCF1 rs1264440 (916-99A>G) and rs4148252 (*1delA), ABCF2 rs3823589 (-43+219C>A) and rs75100208 (368-94C>A) were significantly associated with HCC risk (OR: 1.424, 95%CI: 1.03-1.97, P=0.032; OR: 1.446, 95%CI: 1.04-2.00, P=0.026; OR: 1.635, 95%CI: 1.09-2.46, P=0.018; OR: 1.479, 95%CI: 1.09-2.18, P=0.049, respectively). Patients with any two of the four variant genotype, compared with those with all wild type, revealed elevated HCC risks (OR: 1.657, 95%CI: 1.16-2.37, P=0.006). Importantly, patients with all four variant genotypes demonstrated augmented HCC risk (OR: 2.295, 95%CI: 1.27-4.15, P=0.006). Conclusions: ABCF1 genetic variants rs1264440, rs4148252 and ABCF2 genetic variants rs3823589, rs75100208 were associated with significantly increased HCC risk. Augmented cancer risk was observed among patients possessed all four variant genotypes in ABCF1 and ABCF2. Further mechanistic studies are warranted to comprehend the underlying mechanisms. Citation Format: Philip Chun Yeung, Kelvin Kwok Chai Ng, Tan To Cheung, Charing Ching-Ning Chong, Paul Bo San Lai, Siu Tim Cheung. ABCF1 and ABCF2 genetic variants in association with hepatocellular carcinoma (HCC) risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1436.

Hepatocellular carcinoma (HCC) is a major global health problem and its treatment outcomes are limited by therapeutic resistance. Cancer stem cells are the roots of tumor growth, recurrence, metastasis and treatment resistance. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor well known to promote carcinogenesis in a number of tumors. The present study aims to investigate the role of STAT3 in HCC. Total STAT3 levels were examined by qRT-PCR in patients with primary HCC who underwent curative partial hepatectomy. Elevated STAT3 levels were significantly associated with poor recurrence-free survival and overall survival of HCC patients (log-rank test, P = 0.019 and 0.008, respectively). Immunohistochemistry (IHC) was performed to determine the activation status of STAT3 in HCC. Phosphorylated (p)-Y705 and p-S727 staining was detected in HCC tissues, albeit with varying patterns of expression. To investigate the efficacy of STAT3-targeted therapeutics in HCC, napabucasin, a cancer stemness inhibitor targeting STAT3-driven gene transcription, and the specific small interfering RNA (siRNA) were examined in HCC cell lines Hep3B, HepG2 and Huh7. Both napabucasin and siRNA prominently downregulated RNA and protein levels of total STAT3 and p-STAT3 of HCC cells. Napabucasin reduced viability, induced death, hindered migration, impaired colony and spheroid formation efficiency of HCC cells, as well as lowered expression levels of the cancer stem cell markers granulin-epithelin precursor (GEP) and CD133 in whole genome RNA sequencing analysis. Notably, napabucasin combined with 5-fluorouracil (5-FU) synergistically inhibited cell proliferation and induced apoptosis, suggesting its potential in sensitizing HCC cells to chemotherapeutic agents. In addition, napabucasin diminished the colony and spheroid formation abilities of chemo-resistant HCC cells (acquired resistance to 5-FU with over 10-fold increase) to a similar extent as their parental counterparts, indicating its potency in targeting chemo-resistant HCC cells via cancer stemness inhibition. Furthermore, napabucasin also suppressed HCC tumor growth in vivo, accompanied with reduced total STAT3 and p-STAT3 levels and proliferation (Ki-67). Overall, the present study highlighted the prognostic significance of STAT3 in HCC, and its functional role in the control of chemo-resistance and cancer stemness in HCC through targeted therapeutics. Citation Format: Carol Lee, Elaine Yee-Ling OR, Charing Ching-Ning Chong, Tan To Cheung, Iris Ming-Jing Xu, Linda Wing-Chi Ng, Marcus Hung-Lam Law, Peter Tin-Chung Li, Stephen Lam Chan, Anthony Wing-Hung Chan, Philip Chun Yeung, Kelvin Kwok-Chai Ng, Paul Bo-San Lai, Siu Tim Cheung. STAT3 regulates chemo-resistance and cancer stemness in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4151.

The effect of statins in preventing hepatocellular carcinoma (HCC) recurrence after curative liver resection has been controversial. Some retrospective studies identified perioperative use of statins was associated with significantly lower risk of HCC recurrence and improve recurrence-free survival (RFS) after liver resection, among patients with or without chronic hepatitis viral infection in multivariate survival analysis. However, a recent single-center study enrolled 430 cases in Taiwan revealed that the protective effect of statins was only significant in univariate analysis but not significant in multivariate analyses. To evaluate the effect of statins on the risk of HCC recurrence after curative liver resections, we performed a systematic review and meta-analysis on this topic. A systematic search of Medline, Embase, and Web of Science was conducted through December 2019. Studies were included if they evaluated perioperative exposure to statins, reported the recurrence of HCC after curative resection, and reported hazard ratios (HR) of multivariable analysis by Cox proportional hazards model. Summary HR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 5 studies reporting the recurrence of HCC among 8,586 patients after liver resection, in which 411 of them received perioperative statins treatments. A meta-analysis of the studies showed a significant (39%) reduction in the risk of HCC recurrence among patients who took statins (adjusted HR, 0.61; 95% CI, 0.49-0.76), with no or little heterogeneity among studies (χ2=5.58, df=4, I2=28%). In conclusion, perioperative statins use may improve recurrence-free survival and decrease the risk of HCC recurrence after curative liver resection. Further prospective studies and larger randomized controlled trials (RCTs) are warranted to validate the conclusion. Statin usersNon-statin usersAdjusted Hazard RatioStudyTotalTotalWeightIV, Random, 95%CIYear of publicationWu 2012175439437.6%0.68 (0.53-0.87)2012Lee 2016132207831.2%0.66 (0.49-0.90)2016Kawaguchi 2017317037.0%0.34 (0.12-0.75)2017Nishio 20184360014.5%0.42 (0.25-0.71)2018Young 2019304009.8%0.79 (0.41-1.52)2019Total (95% CI)4118175100.0%0.61 (0.49-0.76)Heterogeneity: Tau2=0.02; Chi2=5.58, df=4 (p=0.23); I2=28%Test for overall effect: Z=4.43 (p Citation Format: Chun Philip Yeung, Siu Tim Cheung, Kwok Chai Kelvin Ng, Bo San Paul Lai, Ching Ning Charing Chong. Statin use associated with reduced risk of hepatocellular carcinoma recurrence following liver resection: A systematic review and meta-analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2345.

We have studied the feasibility of detecting tumor-associated aberrant p16 methylation in the circulation of patients with hepatocellular carcinoma (HCC). We extracted DNA from the tumor tissues and peripheral blood plasma or serum of 22 HCC patients. p16 methylation was found in 73% (16 of 22) of HCC tissues using methylation-specific PCR. Among the 16 cases with aberrant methylation in the tumor tissues, similar changes were also detected in the plasma/serum samples of 81% (13 of 16) of the cases. No methylated p16 sequences were detected in the peripheral plasma/serum of the six HCC cases without these changes in the tumor, in 38 patients with chronic hepatitis/cirrhosis, or in 10 healthy control subjects. These results suggest that circulating liver tumor DNA may be detected using tumor-associated DNA methylation changes. Because methylation abnormalities have been found in many other genes and tumor types, this approach may have implications for the noninvasive detection of a wide variety of cancers.