Comprehensive analysis of m6A modification in immune infiltration, metabolism and drug resistance in hepatocellular carcinoma.

N6-methyladenosine (m6A) is important in regulating mRNA stability, splicing, and translation, and it also contributes to tumor development. However, there is still limited understanding of the comprehensive effects of m6A modification patterns on the tumor immune microenvironment, metabolism, and drug resistance in hepatocellular carcinoma (HCC). In this study, we utilized unsupervised clustering based on the expression of 23 m6A regulators to identify m6A clusters. We identified differential m6A modification patterns and characterized m6A-gene-cluster A, which exhibited poorer survival rates, a higher abundance of Treg cells, and increased expression of TGFß in the tumor microenvironment (TME). Additionally, m6A-gene-cluster A demonstrated higher levels of glycolysis activity, cholesterol metabolism, and fatty acid biosynthesis. We also found that the m6A score was associated with prognosis and drug resistance. Patients with a low m6A score experienced worse prognoses, which were linked to an abundance of Treg cells, upregulation of TGFß, and increased metabolic activity. HCC patients with a higher m6A score showed improved prognosis following sorafenib treatment and immunotherapy. In conclusion, we reveals the association between m6A modification patterns and the tumor immune microenvironment, metabolism, and drug resistance in HCC. Furthermore, the m6A score holds potential as a predictive factor for the efficacy of targeted therapy and immunotherapy in HCC.

KLF4 Suppresses the Progression of Hepatocellular Carcinoma by Reducing Tumor ATP Synthesis through Targeting the Mir-206/RICTOR Axis.

To address the increased energy demand, tumor cells undergo metabolic reprogramming, including oxidative phosphorylation (OXPHOS) and aerobic glycolysis. This study investigates the role of Kruppel-like factor 4 (KLF4), a transcription factor, as a tumor suppressor in hepatocellular carcinoma (HCC) by regulating ATP synthesis. Immunohistochemistry was performed to assess KLF4 expression in HCC tissues. Functional assays, such as CCK-8, EdU, and colony formation, as well as in vivo assays, including subcutaneous tumor formation and liver orthotopic xenograft mouse models, were conducted to determine the impact of KLF4 on HCC proliferation. Luciferase reporter assay and chromatin immunoprecipitation assay were utilized to evaluate the interaction between KLF4, miR-206, and RICTOR. The findings reveal low KLF4 expression in HCC, which is associated with poor prognosis. Both in vitro and in vivo functional assays demonstrate that KLF4 inhibits HCC cell proliferation. Mechanistically, it was demonstrated that KLF4 reduces ATP synthesis in HCC by suppressing the expression of RICTOR, a core component of mTORC2. This suppression promotes glutaminolysis to replenish the TCA cycle and increase ATP levels, facilitated by the promotion of miR-206 transcription. In conclusion, this study enhances the understanding of KLF4's role in HCC ATP synthesis and suggests that targeting the KLF4/miR-206/RICTOR axis could be a promising therapeutic approach for anti-HCC therapeutics.

A novel NHEJ gene signature based model for risk stratification and prognosis prediction in hepatocellular carcinoma.

BACKGROUND: Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC. METHODS: Two cohorts from public database were incorporated into this study. The Kaplan-Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6. RESULTS: A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro. CONCLUSIONS: In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy.

Deep Learning With 3D Convolutional Neural Network for Noninvasive Prediction of Microvascular Invasion in Hepatocellular Carcinoma.

BACKGROUND: Microvascular invasion (MVI) is a critical prognostic factor of hepatocellular carcinoma (HCC). However, it could only be obtained by postoperative histological examination. PURPOSE: To develop an end-to-end deep-learning models based on MRI images for preoperative prediction of MVI in HCC patients who underwent surgical resection. STUDY TYPE: Retrospective. POPULATION: Two hundred and thirty-seven patients with histologically confirmed HCC. FIELD STRENGTH: 1.5 T and 3.0 T. SEQUENCE: Axial T2 -weighted (T2 -w) with turbo spin echo sequence, T2 -Spectral Presaturation with Inversion Recovery (T2 -SPIR), and dynamic contrast-enhanced (DCE) imaging with fat suppressed enhanced T1 high-resolution isotropic volume examination. ASSESSMENT: The patients were randomly divided into training (N = 158) and validation (N = 79) sets. Data augmentation by random rotation was performed on the training set and the sample size increased to 1940 for each MR sequence. A three-dimensional convolutional neural network (3D CNN) was used to develop four deep-learning models, including three single-layer models based on single-sequence, and fusion model combining three sequences. MVI status was obtained from the postoperative pathology reports. STATISTICAL TESTS: The dice similarity coefficient (DSC) and Hausdorff distance (HD) were applied to assess the similarity and reproducibility between the manual segmentations of tumor from two radiologists. Receiver operating characteristic curve analysis was used to evaluate model performance. MVI was identified in 92 (38.8%) patients. Good reproducibility with interobserver DSCs of 0.90, 0.89, and 0.89 and HDs of 4.09, 3.67, and 3.60 was observed for PVP, T2 WI, and T2 -SPIR, respectively. The fusion model achieved an area under the curve (AUC) of 0.81, sensitivity of 69%, and specificity of 79% in the training set and 0.72, sensitivity of 55%, and specificity of 81% in the validation set. DATA CONCLUSION: 3D CNN model may serve as a noninvasive tool to predict MVI in HCC, whereas its accuracy needs to be enhanced with larger cohort. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Long-term outcome for colorectal liver metastases: combining hepatectomy with intraoperative ultrasound guided open microwave ablation versus hepatectomy alone.

OBJECTIVE: To compare the long-term outcome of combining hepatectomy with intraoperative ultrasound (IOUS)-guided open microwave ablation (MWA) versus hepatectomy alone in patients with colorectal cancer liver metastases (CRLM). METHOD: A retrospective analysis of patients with CRLM who underwent hepatectomy alone (HT group; 380 patients) or hepatectomy combined with IOUS-guided open MWA (HT + MWA group; 57 patients) from April 2002 to September 2018 was conducted at our center. A propensity score-matched (PSM) analysis was used to reduce data bias between the two groups. RESULTS: The overall survival (OS) and disease-free survival (DFS) were not significantly different between the two groups after matching. Although intrahepatic recurrence was more frequent in the HT + MWA group in both the whole and matched cohort, the two groups exhibited similar rates of extrahepatic recurrence as well as concomitant intra- and extrahepatic recurrence. A higher number of CRLM (>3), larger maximum-size and absence of response to induction chemotherapy were independent risk factors for OS. CONCLUSION: The oncological outcomes of hepatectomy combined with intraoperative open ablation was not significantly different to hepatectomy alone and should be considered as a safe and fair option for patients with difficultly resectable CRLM.

Surgical Resection versus Re-Ablation for Intrahepatic Recurrent Hepatocellular Carcinoma after Initial Ablation Therapy.

BACKGROUND AND AIMS: Whether surgical resection or repeated ablation should be recommended for intrahepatic recurrent hepatocellular carcinoma (HCC) conforming to the Milan criteria after initial ablation remains unclear. In this study, we compared the outcomes of patients who underwent surgical resection with those who underwent re-ablation for recurrent HCC after initial curative-intent ablation. METHODS: The data of 28 and 98 patients who underwent surgical resection and re-ablation, respectively, for recurrent HCC after initial ablation between January 2003 and 2017 were analyzed using propensity score matching. RESULTS: Before matching, the 1-, 3-, and 5-year overall survival (OS) rates were 95.7, 83.0, and 74.4% for the ablation group, compared to 92.9, 89.1, and 70.9% for the resection group (p = 0.490). The corresponding disease-free survival (DFS) rates were 67.5, 40.1, and 25.6% for the ablation group and were 85.4, 59.9, and 53.3% for the resection group (p = 0.018). After matching, the 1-, 3-, and 5-year OS rates for the ablation and resection group were 95.2, 85.5 and 81.8% versus 96.0, 96.0, and 76.4%, respectively (p = 0.550). The 1-, 3-, and 5-year DFS rates were 58.0, 39.5, and 29.9% for the ablation group and were 95.8, 67.2, and 59.8% for the resection group (p = 0.004). Cox proportional hazards model identified surgical resection as the only significant prognostic factor for DFS but not for OS. CONCLUSION: For intrahepatic recurrent HCC patients after initial ablation, surgical resection could provide better DFS than re-ablation, while no difference in OS was observed between the 2 treatment groups.

Comparison of the prognostic value of inflammation-based scores in early recurrent hepatocellular carcinoma after hepatectomy.

BACKGROUND & AIMS: Inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), Prognostic Nutritional Index (PNI), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and systemic immune-inflammation index (SII), are correlated with the survival of hepatocellular carcinoma (HCC) patients, while remain unclear for recurrent HCC. This study aimed to compare the prognostic value of inflammation-based prognostic scores for post-recurrence survival (PRS) in patients with early recurrent HCC (ErHCC, within 2 years after hepatectomy). METHODS: A total of 580 patients with ErHCC were enrolled retrospectively. The association between the independent baseline and the time-dependent variables and PRS was evaluated by cox regression. The prediction accuracy of the inflammation-based prognostic scores was assessed by time-dependent receiver operating characteristic (ROC) and Harrell's concordance index (C-index) analyses. RESULTS: The GPS, mGPS, PI, PNI, NLR, PLR, LMR and SII were all related to the PRS of ErHCC patients, while only the SII (P < .001) remained an independent predictor for PRS in multivariate analysis (hazard ratio: 1.92, 95% confidence interval: 1.33-2.79). Both the C-index of the SII (0.65) and the areas under the ROC curves showed that the SII score was superior to the other inflammation-based prognostic scores for predicting the PRS of ErHCC patients. CONCLUSIONS: The SII is a useful prognostic indicator for PRS in patients with ErHCC after hepatectomy and is superior to the other inflammation-based prognostic scores in terms of prognostic ability.

Primary tumor location affects recurrence-free survival for patients with colorectal liver metastases after hepatectomy: a propensity score matching analysis.

BACKGROUND: Whether primary tumor location of colorectal cancer (CRC) affects survival of patients after resection of liver metastases remains controversial. This study was conducted to investigate the differences in clinicopathological characteristics and prognosis between right-sided CRC and left-sided CRC patients with liver metastases after hepatectomy. METHODS: From 2002 to 2018, 611 patients with colorectal liver metastases (CRLM) who underwent hepatectomy at our center were reviewed. Primary tumors located from the cecum to transverse colon were defined as right-sided group (n = 141); tumors located from the splenic flexure to rectum were defined as left-sided group (n = 470). Patients were compared between two groups before and after a 1:1 propensity score matching (PSM) analysis. RESULTS: Before PSM, median survival time and 5-year overall survival (OS) rate in right-sided group were 77 months and 56.3%, and those in left-sided group were 64 months and 51.1%, respectively. After PSM, median survival time and 5-year OS rate in right-sided group were 77 months and 55.9%, and those in left-sided group were 58.8 months and 47.3%, respectively. The OS rates did not differ between two groups before and after PSM (P = 0.575, P = 0.453). However, significant different recurrence-free survival (RFS) rate was found before and after PSM between right-sided and left-sided group (P = 0.028, P = 0.003). CONCLUSIONS: Compared to patients with left-sided primary tumors, patients with right-sided primary tumors had a worse RFS but similar OS. Careful preoperative evaluation, intensive preoperative chemotherapy, and frequent follow-up to detect early recurrence might be justified for CRLM patients with right-sided primary tumors.

Lithium Plating and Stripping on Carbon Nanotube Sponge.

Lithium metal is an ideal anode material due to its high specific capacity and low redox potential. However, issues such as dendritic growth and low Coulombic efficiency prevent its application in secondary lithium batteries. The use of three-dimensional (3D) porous current collector is an effective strategy to solve these problems. Herein, commercial carbon nanotube (CNT) sponge is used as a 3D current collector for dendrite-free lithium metal deposition to improve the Coulombic efficiency and the cycle stability of the lithium metal batteries. The high specific surface area of the CNT increases the density of the lithium nucleation sites and ensures the uniform lithium deposition while the "pre-lithiation" behavior of the porous CNT enhances its affinity with the deposited lithium. Meanwhile, the lithium plating/stripping on the sponge maintains high Coulombic efficiency and high cycling stability due to the robust structure of graphitic-amorphous carbon composite in the ether-based electrolyte. Our findings exhibit the feasibility of using CNT sponge as a 3D porous current collector for lithium deposition. They shed light on designing and developing advanced current collectors for the lithium metal electrode and will promote the commercialization of the secondary lithium batteries.

Long non-coding RNA UCA1 promotes breast cancer by upregulating PTP1B expression via inhibiting miR-206.

BACKGROUND: The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) is involved in various cancers and often functions through microRNAs. The pro-survival protein PTP1B is known to play important roles in cancer development. However, the connection between UCA1 and PTP1B in breast cancer is not well studied. METHODS: In this study, we first evaluated the correlation between UCA1 level and PTP1B expression in breast tissues, which showed the expression of PTP1B were much higher in the breast tumor tissues than in the peritumor normal tissues. The UCA1 level was positively associated with PTP1B expression in breast tumor tissues. RESULTS: We observed that UCA1 could up-regulate PTP1B expression in breast cancer cells. We also found that miR-206 could inhibit the expression of PTP1B by directly binding to the 3'-UTR of its mRNA. Interestingly, UCA1 could increase the expression of PTP1B through sequestering miR-206 at post-transcriptional level. The results also suggested that UCA1-induced PTP1B expression facilitated the proliferation of breast cancer cells. CONCLUSIONS: We conclude that UCA1 can up-regulates PTP1B to enhance cell proliferation through sequestering miR-206 in breast cancer. Our finding provides new insights into the mechanism of breast cancer regulation by UCA1, which could be a potential target for breast cancer treatment.Trial registration 2012N5hSYSU48573. Registered at Oct 12, 2012.

Lipiodol deposition in portal vein tumour thrombus predicts treatment outcome in HCC patients after transarterial chemoembolisation.

OBJECTIVE: To study lipiodol deposition in portal vein tumour thrombus (PVTT) in predicting the treatment outcome of hepatocellular carcinoma (HCC) patients after transarterial chemoembolisation (TACE). METHODS: We retrospectively reviewed data from 379 HCC patients with PVTT who underwent TACE as the initial treatment at Sun Yat-Sen University Cancer Center from January 2008 to December 2015. Patients were grouped by positive and negative lipiodol deposition based on the extent of lipiodol deposition in PVTT. The overall survival (OS) and progression-free survival (PFS) were compared between negative and positive lipiodol deposition groups; furthermore, the value of the combinatorial evaluation of tumour responses and lipiodol deposition in PVTT in predicting prognosis was analysed in subgroup patients with stable disease (SD) after TACE. RESULTS: Of the 379 patients, 264 (69.7%) had negative and 115 (30.3%) had positive lipiodol deposition in PVTT after TACE. Multivariate analysis identified positive lipiodol deposition in PVTT as an independent prognostic factor for favourable OS (p = 0.001). The median OS and PFS of negative and positive lipiodol deposition groups were 4.70 vs. 8.97 months (p = 0.001) and 3.1 months vs. 5.8 months (p < 0.001). In subgroup patients, the median OS and PFS of negative and positive lipiodol deposition groups were 4.7 months vs. 10.5 months (p < 0.001) and 3.5 months vs. 7.0 months (p < 0.001), respectively. CONCLUSIONS: The patients with positive lipiodol deposition in PVTT had a longer OS than those with negative lipiodol deposition. Furthermore, the positive lipiodol deposition in PVTT can further differentiate HCC patients with favourable prognosis from SD patients. KEY POINTS: • Lipiodol deposition in PVTT is a prognostic indicator for HCC patients after TACE treatment. • Positive lipiodol deposition in PVTT is associated with a better prognosis.

Nomogram to Predict Survival of Patients With Recurrence of Hepatocellular Carcinoma After Surgery.

BACKGROUND & AIMS: We aimed to establish and validate a nomogram to predict survival at 2 and 5 years after recurrence of hepatocellular carcinoma (HCC) in patients who have undergone curative resection. METHODS: We developed a nomogram using data from a training cohort of 638 patients (most with hepatitis B virus infection) with recurrence of HCC after curative resection at Sun Yat-sen University Cancer Center, in Guangzhou, China from 2007 through 2013. The median follow-up time was 39.7 months. Patients were evaluated every 3-4 months for the first 2 years after resection and every 3-6 months thereafter. The nomogram was based on variables independently associated with survival after HCC recurrence, including antiviral treatment; albumin-bilirubin grade and alpha-fetoprotein level at recurrence; time from primary resection to recurrence; size, site, number of recurrences; and treatment for recurrence. We validated the nomogram using data from an independent internal cohort of 213 patients treated at the same institution and an external cohort of 127 patients treated at 2 other centers in China, from 2002 through 2009. The predictive accuracy of the nomogram was measured using Harrell's concordance index (C index) and compared with the Barcelona Clinic Liver Cancer staging system of recurrence. RESULTS: Our nomogram predicted survival of patients in the training cohort with a C-index of 0.797 (95% CI, 0.765-0.830)-greater than that of the Barcelona Clinic Liver Cancer staging system for recurrence (C-index score, 0.713; 95% CI, 0.680-0.745) (P < .001). This nomogram accurately stratified patients into subgroups with predicted long, medium, and short survival times: the proportions of patients in each group who survived 2 years after HCC recurrence were 91.2%, 67.6%, and 23.8%; the proportions of patients in each group who survived 5 years after HCC recurrence were 74.9%, 53.3%, and 9.1%. Our nomogram predicted patient survival times with C-index scores of 0.756 (95% CI, 0.703-0.808) in the internal validation cohort and 0.747 (95% CI, 0.701-0.794) in the external validation cohorts. CONCLUSIONS: We developed a nomogram to determine the probability of survival, at different time points, of patients with recurrence of HCC (most with hepatitis B virus infection), after curative resection and validated it internally and externally.

Nomograms for Pre- and Postoperative Prediction of Long-term Survival for Patients Who Underwent Hepatectomy for Multiple Hepatocellular Carcinomas.

OBJECTIVES: To develop prognostic nomograms for patients undergoing hepatectomy for multiple hepatocellular carcinomas (mHCCs). BACKGROUND: The prognostic prediction after hepatectomy for mHCCs has not been well established. METHODS: A training cohort (n = 540) was analyzed to construct 2 nomograms based separately on data obtained before and after hepatectomy for mHCCs at the Eastern Hepatobiliary Surgery Hospital between 2000 and 2006. The internal and external validations were performed in 2 independent cohorts (n = 180 each) collected from the Eastern Hepatobiliary Surgery Hospital between 2007 and 2010 and the Sun Yat-Sen University between 2000 and 2007. The predictive accuracy was measured by concordance index (C-index) and calibration curve. RESULTS: Serum α-fetoprotein level, hepatitis B virus deoxyribonucleic acid load, end-stage liver disease score, tumor number, total tumor diameter, and the ratio of largest to smallest tumor diameter were incorporated into the preoperative nomogram for overall survival (OS) prediction. In addition to these variables, microvascular invasion, tumor capsule, type of hepatectomy, and local invasion/metastasis were incorporated into the postoperative nomogram. All calibration curves for probability of OS fitted well. In the training cohort, the preoperative nomogram achieved a C-index of 0.75 (95% confidence interval, 0.72-0.78) in predicting OS and accurately stratified patients into 4 prognostic subgroups (5-year OS rates: 65.9%, 46.3%, 29.6%, and 4.1%, P < 0.001). The postoperative nomogram had a C-index of 0.80, which was higher than those of the 4 conventional staging systems (0.53-0.62). These results were supported by the internal and external validations. CONCLUSIONS: The 2 nomograms showed accurate pre- and postoperative prediction of posthepatectomy prognosis in patients with mHCCs.

The role of clinically significant portal hypertension in hepatic resection for hepatocellular carcinoma patients: a propensity score matching analysis.

BACKGROUND: Whether portal hypertension (PHT) is an appropriate contraindication for hepatic resection (HR) in hepatocellular carcinoma (HCC) patient is still under debate. AIMS: Our aim was to assess the impact of clinically significant PHT on postoperative complication and prognosis in HCC patients who undergo HR. METHODS: Two hundred and nine HCC patients who underwent HR as the initial treatment were divided into two groups according to the presence (n = 102) or absence (n = 107) of clinically significant PHT. Propensity score matching (PSM) analysis was used to compare postoperative outcomes and survival. RESULTS: Before PSM, PHT patients had higher rates of postoperative complication (43.1% vs. 23.4%; P = 0.002) and liver decompensation (37.3% vs. 17.8%; P = 0.002) with similar rates of recurrence-free survival (RFS; P = 0.369) and overall survival (OS; P = 0.205) compared with that of non-PHT patients. However, repeat analysis following PSM revealed similar rates of postoperative complication (32.2% vs. 39.0%; P = 0.442), liver decompensation (25.4% vs. 32.2%; P = 0.416), RFS (P = 0.481) and OS (P = 0.417; 59 patients in each group). Presence of PHT was not associated with complication by logistic regression analysis, or with overall survival by Cox regression analysis. CONCLUSIONS: The presence of clinically significant PHT had no impact on postoperative complication and prognosis, and should not be regarded as a contraindication for HR in HCC patients.

Hepatectomy Versus Hepatectomy With Lymphadenectomy in Hepatocellular Carcinoma: A Prospective, Randomized Controlled Clinical Trial.

GOALS AND BACKGROUND: The role of preventive lymphadenectomy has not yet been determined for hepatocellular carcinoma (HCC) patients. We designed a study to evaluate the effect of hepatectomy combined with preventive lymphadenectomy on HCC patients. STUDY: Patients were randomly divided into group A (treated with hepatectomy alone) and group B (underwent hepatectomy combined with lymphadenectomy). The postoperative complications and oncologic prognoses were analyzed. RESULTS: Of the 85 patients enrolled into this study, 79 cases (38 in group A and 41 in group B) were pathologically confirmed to have HCC and received curative resection. One hundred and sixteen lymph nodes were dissected and evaluated as negative by the pathologist. The 12-, 36-, and 60-month disease-free survival rates of group A were 81.6%, 68.4%, and 63.2%, respectively, whereas they were 78.0%, 65.9%, and 63.4%, respectively, for group B. The 12-, 36-, and 60-month overall survival rates in group A were 94.7%, 78.9%, and 65.8%, respectively, whereas they were 87.8%, 78.0%, and 70.7%, respectively, in group B. The differences in the disease-free survival and overall survival between the 2 groups were not statistically significant according to the log-rank test (P=0.811 and P=0.881, respectively). The difference in the surgical complication rate between groups A and B was not statistically significant (47.4% vs. 36.6%, P=0.332). CONCLUSIONS: Although hepatectomy combined with regional lymphadenectomy is a safe procedure, preventive lymphadenectomy may not decrease the rate of tumor recurrence nor improve the prognosis in early-stage HCC patients.

SPOCK1 is regulated by CHD1L and blocks apoptosis and promotes HCC cell invasiveness and metastasis in mice.

BACKGROUND & AIMS: Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) is an SNF2-like transcription factor involved in the development of human hepatocellular carcinoma (HCC). Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is up-regulated by CHD1L; we investigated its role in hepatocellular carcinogenesis. METHODS: We investigated interactions between SPOCK1 and CHD1L using electrophoretic mobility shift and luciferase reporter assays. Levels of SPOCK1 messenger RNA (mRNA) and protein were measured in samples of HCC and adjacent nontumor liver tissues (135 pairs) and compared using Pearson correlation coefficients. Effects of SPOCK1 overexpression and silencing were determined in HCC cell lines (QGY-7703, PLC-8024, BEL-7402, and QGY-7701). RESULTS: The CHD1L protein bound directly to the promoter region (nt-1662 to +34) of SPOCK1 and activated transcription. Levels of SPOCK1 mRNA and protein were increased in 60% of human HCC samples, compared with nontumor live tissues, and was associated significantly with clinical stage. Levels of SPOCK1 mRNA were increased among tumors that became metastatic, compared with those that did not, and among patients with shorter overall and disease-free survival times. Ectopic expression of SPOCK1 in HCC cells increased proliferation, foci formation, and colony formation in soft agar; these cells also formed larger xenograft tumors, more rapidly, in nude mice than control HCC cells. Silencing SPOCK1 expression with short hairpin RNA had the opposite effects. We found that SPOCK1 prevents apoptosis of HCC cells by activating Akt, to block release of cytochrome c and activation of caspase-9 and caspase-3; these effects were reversed with an Akt inhibitor. HCC cells that overexpressed SPOCK1 expressed higher levels of matrix metallopeptidase 9, were more invasive in Matrigel assays, and formed more metastatic nodules in immunodeficient mice than control HCC cells. CONCLUSIONS: CHD1L activates expression of SPOCK1, which activates Akt signaling to block apoptosis and invasion by HCC cells, in culture and in mice. Levels of SPOCK1 increase with progression of human HCC. SPOCK1 might be used as a prognostic factor or therapeutic target.

Early recurrence of hepatocellular carcinoma in patients after ablation and resection: A propensity score analysis.

BACKGROUND: Early recurrence (ER, recurrence within 2 years) is common in hepatocellular carcinoma (HCC) patients after ablation and resection. We aimed to compare ER and assess the associated risk factors. METHODS: We collected data from patients underwent resection (1,235) or ablation (517) for early HCC (solitary tumor ≤5 â€‹cm). Baseline of patients were matched using propensity score matching. RESULTS: In the matched cohort of 690 patients, the ablation group had a higher ER rate (37.4% vs. 19.4%; P < .001) than the resection group. Patients with ER had worse overall survival (OS) than those without ER in both the ablation (5-year OS: 60.4% vs. 86.7%) and resection groups (5-year OS: 59.2% vs. 88.1%). Ablation treatment was identified as an independent adverse prognostic factor for ER (hazard ratio: 2.751, P < .001). Resection conferred a significant favorable OS than ablation (2-year: 95.4% vs. 90.9%; 5-years: 83.8% vs. 77.0%). CONCLUSIONS: Resection was superior to ablation in minimizing the risk of ER and offering a better OS for patients with early HCC.

m6A-mediated lnc-OXAR promotes oxaliplatin resistance by enhancing Ku70 stability in non-alcoholic steatohepatitis-related hepatocellular carcinoma.

BACKGROUND: The escalating prevalence of metabolic diseases has led to a rapid increase in non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (NASH-HCC). While oxaliplatin (OXA)-based hepatic arterial infusion chemotherapy (HAIC) has shown promise in advanced-stage HCC patients, its efficacy in NASH-HCC remains uncertain. This study aims to assess the effectiveness of OXA-based HAIC and elucidate the mechanisms underlying OXA resistance in NASH-HCC. METHODS: The key lncRNAs were screened through RNA-seq analysis of NASH/non-NASH and OXA-sensitive/OXA-resistant (OXA-S/R) HCC tissues. The biological functions of the lnc-OXAR (OXA resistance-related lncRNA in NASH-HCC) in NASH-HCC were verified through a series of in vitro and in vivo experiments. The molecular mechanism of lnc-OXAR was elucidated by fluorescence in situ hybridization, immunoprecipitation-mass spectrometry (FISH), Immunoprecipitation-Mass Spectrometry (IP-MS), RNA pulldown, RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and a dual-luciferase reporter assay. RESULTS: NASH-HCC exhibited reduced responsiveness to OXA-based HAIC compared to non-NASH HCC. We identified and validated a novel transcript namedlnc-OXAR, which played a crucial role in conferring OXA resistance to NASH-HCC. Inhibition of lnc-OXAR suppressed HCC cell growth and restored OXA sensitivity both in NASH-HCC mouse models and in vitro. Mechanistically, lnc-OXAR recruited Ku70 and cystatin A (CSTA), preventing Ku70 degradation and facilitating DNA double-strand break (DSB) repair, thereby promoting OXA resistance in NASH-HCC. Additionally, WTAP-mediated m6A modification enhanced the stability of lnc-OXAR in an IGF2BP2-dependent manner. Notably, silencing lnc-OXAR significantly enhanced the response to OXA in patient-derived xenograft (PDX) models derived from NASH-HCC. CONCLUSIONS: The reduced responsiveness of NASH-HCC to OXA treatment can be attributed to the upregulation of lnc-OXAR. Our findings provide a rationale for stratifying HCC patients undergoing OXA-based HAIC based on etiology. Lnc-OXAR holds promise as a novel target for overcoming OXA resistance in NASH-HCC and improving prognosis.

Atezolizumab and bevacizumab plus transarterial chemoembolization and hepatic arterial infusion chemotherapy for patients with high tumor burden unresectable hepatocellular carcinoma: A multi-center cohort study.

BACKGROUND: Though atezolizumab plus bevacizumab (A+B) offer promise for unresectable hepatocellular carcinoma (uHCC) treatment, the response rate remains suboptimal. Our previous studies highlighted the potential of transarterial chemoembolization (TACE) when combined with FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) in HCC treatment. This study aims to evaluate the safety and efficacy of A+B plus TACE-HAIC for high tumor burden uHCC (HTB-uHCC). METHODS: This three-center retrospective study involved 82 HTB-uHCC patients administered with TACE-HAIC followed by A+B. We characterized HTB-uHCC patients as those surpassing the up-to-11 criteria, exhibiting VP 3-4, or presenting extrahepatic metastases. The primary outcomes were the objective response rate (ORR) and progression-free survival (PFS). Secondary outcomes encompassed the incidence of treatment-related adverse events (TRAEs) and overall survival (OS). RESULTS: Employing the mRECIST criteria, the ORR was 62.2 %, wherein 18 (22.0 %) patients achieved complete response, 33 (40.2 %) demonstrated partial response, 21 (25.6 %) maintained stable disease, and 10 (12.2 %) exhibited disease progression. Impressively, 11 (13.4 %) patients were converted to resectable HCC and underwent curative hepatectomy. The median PFS was 10.1 months (95 % CI, 8.4 to NA), and the median OS was still pending. At the one-year mark, the OS and PFS rates were 92.8 % (95 % CI, 86.1 to 100.0) and 42.9 % (95 % CI, 31.3 to 58.7), respectively. 79 (96.3 %) experienced TRAEs, and 39 (47.6 %) had grade 3-4 TRAEs, though no treatment-related death was recorded. CONCLUSIONS: The findings underscore the potential of the A+B and TACE-HAIC combined treatment for HTB-uHCC patients, marking it as a viable therapeutic option, given its potent efficacy and tolerable safety profile.

PD-L1 inhibitor versus PD-1 inhibitor plus bevacizumab with transvascular intervention in unresectable hepatocellular carcinoma.

Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.