Multiomics analyses and machine learning of nuclear receptor coactivator 6 reveal its essential role in hepatocellular carcinoma.

Nuclear receptor coactivator 6 (NCOA6), a coactivator of numerous nuclear receptors and transcription factors, regulates multiple critical cellular functions. Nuclear receptor coactivator 6 is dysregulated in various cancers, including hepatocellular carcinoma (HCC); however, its role remains largely unknown. Here we reported that NCOA6 was highly expressed in HCC compared to the adjacent liver tissue, and NCOA6 overexpression was significantly correlated with poor HCC prognosis. Experiments revealed that the knockdown of NCOA6 damaged the proliferation, migration, and invasion of HCC cells. Multiomics and immune infiltration analyses showed a close relationship between NCOA6 expression, multiple cancer-related malignant pathways, and the immunosuppressive microenvironment. Finally, we established an effective NCOA6-related microRNA (miRNA) signature to distinguish HCC from hepatitis\liver cirrhosis patients. To the best of our knowledge, this study is the first to provide a comprehensive analysis of NCOA6 expression in HCC. We found that NCOA6 plays an important role in HCC development and has a potential mechanism of action. Establishing an NCOA6-related miRNA signature will help develop novel diagnostic strategies for HCC patients.

Dimeric oxyberberine CT4-1 targets LINC02331 to induce cytotoxicity and inhibit chemoresistance via suppressing Wnt/ß-catenin signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a type of cancer characterized by high recurrence rates. Overcoming chemoresistance can reduce HCC recurrence and improve patients' prognosis. This work aimed to identify HCC chemoresistance-associated long non-coding RNA (lncRNA) and find an effective drug targeting the identified lncRNA for ameliorating the chemoresistance. In this investigation, bioinformatics analysis based on The Cancer Genome Atlas revealed a new chemoresistance index and suggested LINC02331 as an HCC chemoresistance and patients' prognosis-associated lncRNA that served as an independent prognostic indicator. Moreover, LINC02331 promoted DNA damage repair, DNA replication, and epithelial-mesenchymal transition as well as attenuated cell cycle arrest and apoptosis through regulating Wnt/ß-catenin signaling, thus stimulating HCC resistance to cisplatin cytotoxicity, proliferation, and metastasis. Interestingly, we developed a novel oxidative coupling approach to synthesize a dimeric oxyberberine CT4-1, which exerted superior anti-HCC activities without obvious side effects measured by in vivo mice model and could downregulate LINC02331 mice model and could downregulate LINC02331 to mitigate LINC02331-induced HCC progression by suppressing Wnt/ß-catenin signaling. RNA sequencing analyses verified the involvement of CT4-1-affected differential expression genes in dysregulated pathways and processes, including Wnt, DNA damage repair, cell cycle, DNA replication, apoptosis, and cell adhesion molecules. Furthermore, CT4-1 was demonstrated to be an effective cytotoxic drug in ameliorating HCC patients' prognosis with a prediction model constructed based on RNA-sequencing data from CT4-1-treated cancer cells and public cancer database. In summary, HCC chemoresistance-associated LINC02331 independently predicted poor patients' prognosis and enhanced HCC progression by promoting resistance to cisplatin cytotoxicity, proliferation, and metastasis. Targeting LINC02331 by the dimeric oxyberberine CT4-1 that exhibited synergistic cytotoxicity with cisplatin could alleviate HCC progression and improve patients' prognosis. Our study identified LINC02331 as an alternative target and suggested CT4-1 as an effective cytotoxic drug in HCC treatment.

TGF-ß1 induced deficiency of linc00261 promotes epithelial-mesenchymal-transition and stemness of hepatocellular carcinoma via modulating SMAD3.

Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the metastasis and recurrence of hepatocellular carcinoma (HCC). A kinds of lncRNAs were found to be involved in regulating epithelial-mesenchymal transition (EMT) or stem-like traits in human cancers, however, the molecular mechanism and signaling pathways targeting EMT and stemness remains largely unknown. Previously, we found that linc00261 was down-regulated in HCC and associated with multiple worse clinical pathological parameters and poor prognosis. Here, we show that linc00261 was down-regulated in TGF-ß1 stimulated cells, and forced expression of linc00261 attenuated EMT and stem-like traits in HCC. Linc00261 also inhibited the tumor sphere forming in vitro and decreased the tumorigenicity in vivo. Furthermore, we revealed that linc00261 suppressed the expression and phosphorylation of SMAD3 (p-SMAD3), which could be core transcriptional modulator in TGF-ß1 signaling mediated EMT and the acquisition of stemness traits. A negative correlation between linc00261 and p-SMAD3 was determined in HCC samples. Conclusion: Our study revealed that linc00261 suppressed EMT and stem-like traits in HCC cells by inhibiting TGF-ß1/SMAD3 signaling.

CMTM6 promotes migration, invasion, and EMT by interacting with and stabilizing vimentin in hepatocellular carcinoma cells.

BACKGROUND: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) has been associated with the development in many kinds of cancers. However, the roles of CMTM6 in hepatocellular carcinoma (HCC) are largely unknown. Thus, the present study aimed to investigate the function of CMTM6 in HCC. METHODS: We analysed CMTM6 levels and functions using human HCC cell lines, paired HCC and adjacent non-tumorous tissues, and a tissue microarray. CMTM6 expression was silenced using short hairpin RNAs and its was overexpressed from a lentivirus vector. CMTM6 mRNA and protein levels were determined using quantitative real-time reverse transcription PCR and western blotting, respectively. Proliferation, colony formation, migration, and invasion were assessed using a Cell counting kit-8, colony formation, wound-healing, and Matrigel invasion assays, respectively. Immunohistochemistry was used to score the expression of CMTM6 in tissue samples. The localization and binding partners of CMTM6 were investigated using immunofluorescence and coimmunoprecipitation experiments, respectively. A mouse xenograft model was used for in vivo studies. RESULTS: Compared with that in adjacent, non-cancerous tissue, Here, CMTM6 levels were increased in HCC tissue samples. Silencing of CMTM6 suppressed the proliferation, migration, and invasion of HCC cells. Conversely, CMTM6 overexpression enhanced HCC cell invasion, migration, and proliferation. Mechanistically, CMTM6 physically interacts with and stabilizes vimentin, thus inducing epithelial-mesenchymal transition (EMT), which promotes proliferation, migration and invasion. Importantly, in HCC tissues, CMTM6 expression correlated positively with vimentin levels. Poor prognosis of HCC was associated significantly with higher CMTM6 expression. CONCLUSIONS: CMTM6 has an important function in HCC proliferation, migration, and invasion, via its interaction with and stabilization of vimentin. CMTM6 might represent a potential biomarker and therapeutic target to treat HCC.

Deficiency of pseudogene UPAT leads to hepatocellular carcinoma progression and forms a positive feedback loop with ZEB1.

Hepatocellular carcinoma (HCC) is a common disease worldwide. Accumulating reports have evidenced the internal connection between epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), as well as their significance in metastasis and post-operative recurrence. In this study, we investigated an interesting ubiquitin-proteasome pathway associated pseudogene of AOC4, also known as UPAT, and showed that it was downregulated in 39.78% (37/93) of patients with hepatitis B virus (HBV)-related HCC. Downregulation of UPAT was associated with multiple worse clinicopathological parameters, as well as decreased recurrence-free survival (RFS). In vitro and in vivo assays found that overexpression of UPAT significantly suppressed cellular migration, invasion, EMT processes, and CSC properties. Mechanistic studies showed that UPAT promoted ZEB1 degradation via a ubiquitin-proteasome pathway and, in contrast, ZEB1 transcriptionally suppressed UPAT by binding to multiple E-box (CACCTG) elements in the promoter region. Moreover, UPAT was negatively correlated with ZEB1 protein in HCC tissues, their combined expression discriminated RFS outcomes for patients with HBV-related HCC. These data on the UPAT-ZEB1 circuit-mediated pathway will further knowledge on EMT and CSCs, and may help to develop novel therapeutic approaches for the prevention of HCC metastasis.

MicroRNA-214 suppresses cell proliferation and migration and cell metabolism by targeting PDK2 and PHF6 in hepatocellular carcinoma.

MiR-214 has been reported to act as a tumor suppressor or oncogene involved in various malignancies. However, the biological functions and molecular mechanisms of miR-214 in hepatocellular carcinoma (HCC) still remain unclear. Previous studies suggest that pyruvate dehydrogenase kinase 2 (PDK2) and plant homeodomain finger protein 6 (PHF6) may be involved in some tumor cell proliferation and migration. Therefore, we studied the relationship between PDK2/PHF6 and miR-214. The expression of miR-214, PDK2, and PHF6 was determined by quantitative real-time polymerase chain reaction in HCC tissues and cell lines. The Luciferase reporter assay was used to confirm the interaction between miR-214 and PDK2/PHF6. Cell proliferation, apoptosis, and migration were evaluated by cell counting kit-8 assay, flow cytometry, and transwell assay, respectively. The expressions levels of α-smooth muscle actin (α-SMA) and E-cadherin were detected via immunofluorescence assay. Here, we found that the expression of miR-214 decreased in HCC and was negatively correlated with PDK2 and PHF6. Moreover, PDK2 and PHF6 were the direct targets of miR-214 in HCC cells. Functional analysis showed that knockdown of PDK2 or PHF6 as well as miR-214 overexpression significantly suppressed cell proliferation and migration in HCC cells. Furthermore, we found that the suppression of cell proliferation and migration through PDK2 or PHF6 knockdown could be partially reversed by miR-214 down-regulation. Moreover, we demonstrated a decrease of mesenchymal cell marker α-SMA and increase of the epithelial marker E-cadherin after miR-214 overexpression, PDK2 knockdown or PHF6 knockdown, respectively, which also suggested that cell proliferation and migration were suppressed. Additionally, lactate and pyruvic acid production experiments confirmed miR-214 could suppress the HCC cell lactate and pyruvic acid levels by down-regulating PDK2/PHF6. In conclusion, MiR-214 may act as a tumor suppressor gene, presenting its suppressive role in cell proliferation and migration of HCC cells by targeting PDK2 and PHF6, and might provide a potential therapy target for patients with HCC.

Frizzled 2-induced epithelial-mesenchymal transition correlates with vasculogenic mimicry, stemness, and Hippo signaling in hepatocellular carcinoma.

Prior observation has indicated that Frizzled 2 (FZD2)-induced epithelial-mesenchymal transition (EMT) could be a key step in metastasis and early recurrence of hepatocellular carcinoma (HCC). However, the mechanism underlying tumor development and progression due to aberrant FZD2 expression is poorly defined. Here, we provide evidence that FZD2 is a driver for EMT, cancer stem cell properties, and vasculogenic mimicry (VM) in HCC. We found that FZD2 was highly expressed in two cohorts of Chinese hepatitis B virus-related HCC patients, and that high FZD2 expression was associated with poor prognosis. Concerning the mechanism, gain- and loss-of-function experiments showed the oncogenic action of FZD2 in HCC cell proliferation, apoptosis, migration, and invasion. Further investigations in vitro and in vivo suggested that FZD2 promotes the EMT process, enhances stem-like properties, and confers VM capacity to HCC cells. Notably, integrative RNA sequencing analysis of FZD2-knockdown cells indicated the enrichment of Hippo signaling pathway. Taken together, our data suggest for the first time that FZD2 could promote clinically relevant EMT, CD44+ stem-like properties, and the VM phenotype in HCC involving a potential Hippo signaling pathway-dependent mechanism, and should be considered as a promising therapeutic target for the treatment of HCC.

mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation.

Aging is associated with an increased incidence of venous thromboembolism (VTE), resulting in significant morbidity and mortality in the elderly. Platelet hyperactivation is linked to aging-related VTE. However, the mechanisms through which aging enhances platelet activation and susceptibility to VTE are poorly understood. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) signaling is essential for aging-related platelet hyperactivation and VTE. mTORC1 was hyperactivated in platelets and megakaryocytes (MKs) from aged mice, accompanied by elevated mean platelet volume (MPV) and platelet activation. Inhibition of mTORC1 with rapamycin led to a significant reduction in susceptibility to experimental deep vein thrombosis (DVT) in aged mice (P < .01). To ascertain the specific role of platelet mTORC1 activation in DVT, we generated mice with conditional ablation of the mTORC1-specific component gene Raptor in MKs and platelets (Raptor knockout). These mice developed markedly smaller and lighter thrombi, compared with wild-type littermates (P < .01) in experimental DVT. Mechanistically, increased reactive oxygen species (ROS) production with aging induced activation of mTORC1 in MKs and platelets, which, in turn, enhanced bone marrow MK size, MPV, and platelet activation to promote aging-related VTE. ROS scavenger administration induced a significant decrease (P < .05) in MK size, MPV, and platelet activation in aged mice. Our findings collectively demonstrate that mTORC1 contributes to enhanced venous thrombotic susceptibility in aged mice via elevation of platelet size and activation.

Circulating Tumor Cell Phenotype Indicates Poor Survival and Recurrence After Surgery for Hepatocellular Carcinoma.

BACKGROUND: Circulating tumors cells (CTCs) may be a promising prognostic marker for patients with malignant tumors. However, there are few reports regarding its value for hepatocellular carcinoma (HCC) patients. AIMS: To investigate CTCs with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for HCC patients. METHODS: Peripheral blood samples were obtained from 165 HCC patients before radical surgery. CTCs were isolated via the CanPatrol CTC enrichment technique and classified using epithelial-mesenchymal transition (EMT) markers. The relationship of CTC phenotype with clinicopathological factors and HCC recurrence in patients was analyzed. RESULTS: CTC-positive status (count ≥ 2/5 mL) was found in 70.9% of the 165 HCC patients. Increased CTC number was more common in patients with higher AFP levels, multiple tumors, advanced TNM and BCLC staging, and presence of embolus or microembolus (P < 0.05). CTCs heterogeneity was noted using EMT markers. Mesenchymal CTCs were significantly correlated with high AFP levels, multiple tumors, advanced TNM and BCLC stage, presence of embolus or microembolus, and earlier recurrence (P < 0.05). The presence of mesenchymal CTCs predicted the shortest relapse-free survival, followed by mixed phenotypic CTCs, and then epithelial CTCs (P < 0.001). CONCLUSION: CTC phenotype may serve as a prognostic indicator for HCC patients. CTCs assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.

Loss of tumor suppressor miR-126 contributes to the development of hepatitis B virus-related hepatocellular carcinoma metastasis through the upregulation of ADAM9.

Hepatocellular carcinoma is the most common histological type of primary liver cancer, which represents the second leading cause of cancer-related mortality. MiR-126 was reported to be downregulated in hepatocellular carcinoma tissues, compared with its levels in noncancerous tissues. However, baseline miR-126 expression levels in hepatitis B virus-related hepatocellular carcinoma patients who did not undergo pre-operational treatment remains unknown since hepatitis B virus infection and pre-operational transcatheter arterial chemoembolization were shown to upregulate miR-126 expression. Here, we demonstrated that miR-126 is generally downregulated in a homogeneous population of pre-operational treatment-naïve hepatitis B virus-related hepatocellular carcinoma patients (84.0%, 84/100), and its expression is significantly associated with pre-operational alpha-fetoprotein levels ( p < 0.05), microvascular invasion ( p < 0.05), tumor metastasis ( p < 0.05), as well as early recurrence (12 months after surgery; p < 0.01). Furthermore, the results of our study revealed that miR-126 is negatively correlated with ADAM9 expression in hepatitis B virus-related hepatocellular carcinoma patients. Overexpression of miR-126 was shown to attenuate ADAM9 expression in hepatocellular carcinoma cells, which subsequently inhibits cell migration and invasion in vitro. In addition, Cox proportional hazards regression model analysis showed that ADAM9 levels, tumor number, microvascular invasion, and tumor metastasis rate represent independent prognostic factors for shorter recurrence-free survival. In conclusion, we demonstrated that the loss of tumor suppressor miR-126 in hepatitis B virus-related hepatocellular carcinoma cells contributes to the development of metastases through the upregulated expression of its target gene, ADAM9. MiR-126-ADAM9 pathway-based therapeutic targeting may represent a novel approach for the inhibition of hepatitis B virus-related hepatocellular carcinoma metastases.

A different inhibitor is required for overcoming entecavir resistance: a comparison of four rescue therapies in a retrospective study.

AIMS: Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance. METHODS: A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared. RESULTS: There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2  = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ2  = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log10 IU ml-1 , -2.16 ± 0.81 log10 IU ml-1 , -1.17 ± 1.23 log10 IU ml-1 and -2.49 ± 1.10 log10 IU ml-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence. CONCLUSIONS: TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.

Risk Factors for Worsening of Acute Pancreatitis in Patients Admitted with Mild Acute Pancreatitis.

BACKGROUND The aim of the present study was to investigate risk factors for developing more severe pancreatitis, including moderately severe (MSAP) and severe acute pancreatitis (SAP), in patients admitted with mild acute pancreatitis (MAP). MATERIAL AND METHODS Patients admitted with MAP to our hospital from March 2013 to May 2016 were included and prospectively evaluated. Possible risk factors for developing MSAP or SAP were age, blood glucose level on admission, etiology, sex, Ranson score, amylase level, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores, C-reactive protein (CRP) level, serum calcium level, visceral fat area (VFA), body mass index (BMI), whether this was the first episode of AP, and method of administration of octreotide. The effects of variables for developing MSAP or SAP were evaluated using univariate and multivariate logistic regression models. Mortality, hospital duration, and rate of ICU transfer of patients were compared between patients who developed MSAP or SAP and patients who did not. RESULTS A total of 602 patients admitted with MAP were recruited into this study (256 men and 346 women). Seventy-four patients (12.3%) developed MSAP or SAP. According to univariate logistic regression analyses, the results indicated that there were 5 significant differences between patients who developed MSAP or SAP and those who did not: VFA (>100 cm²) (p=0.003), BMI (≥25 kg/m²) (p=0.001), Ranson score(p=0.004), APACHE-II (≥5) (p=0.001), and blood glucose level on admission (>11.1 mmol/L) (p=0.040). Further multivariate logistic regression analyses revealed that BMI (≥25 kg/m²) (p=0.005), APACHE-II (≥5) (p=0.001), and blood glucose level on admission (>11.1 mmol/L) (p=0.004) were independent risk factors for developing MSAP or SAP in patients admitted with MAP. Moreover, patients who developed MSAP or SAP had a mortality rate of 5.4%. CONCLUSIONS Significant risk factors for developing MSAP or SAP in patients admitted with MAP included BMI (≥25 kg/m²), APACHE-II (≥5), and blood glucose level on admission (>11.1 mmol/L). These factors should be used in the prediction of more severe pancreatitis in patients admitted with MAP.

TPX2 Level Correlates with Hepatocellular Carcinoma Cell Proliferation, Apoptosis, and EMT.

BACKGROUND: Targeting protein for Xklp2 (TPX2) is a microtubule-associated protein involved in targeting the motor protein Xklp2 to microtubules. TPX2 overexpression plays a key role in the progression of human cancers. But the underlying mechanism remains unclear. AIMS: This study aimed to investigate the effects and mechanisms of TPX2 on the cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). METHODS: The tissue TPX2 mRNA and protein were assessed by quantitative reverse transcriptase PCR and immunoblot. Cell proliferation, cell cycle, apoptosis, and invasion were determined by CCK-8, FACS, TdT-UTP nick end-labeling, and transwell assays. Immunoblotting was performed to detect the expression of target proteins. RESULTS: TPX2 was highly expressed in tumor tissues compared with non-tumoral tissues, and TPX2 overexpression was positively correlated with poor prognosis. Knockdown TPX2 effectively reduced cell growth, G2/M arrest, induced apoptosis and cell death, and inhibited EMT. Mechanistically, in the TPX2-siRNA-treated groups, cell-cycle-related proteins cyclin A1, cyclin B1, cyclin E1, and cdk4 were up-regulated, while cyclin D1, cdk2, and p21 proteins were down-regulated. Cell-apoptosis-related proteins Bax, p53, caspase-3, and caspase-8 levels were increased. EMT-related proteins E-cadherin was up-regulated, while N-cadherin, ß-catenin, MMP-9, MMP-2, and Slug were down-regulated. We also found that knockdown TPX2 in HCC cell lines caused a significant decrease in the level of p-Akt and p-ERK which are important signaling pathways in tumor formation. CONCLUSIONS: TPX2 expression is associated with proliferation, apoptosis, and EMT in hepatocellular carcinoma cell and patients.

Expression and Clinical Pathological Significance of miR-200a in Concurrent Cholangiocarcinoma Associated with Hepatolithiasis.

BACKGROUND Approximately 2-10% of the patients with hepatolithiasis may develop cholangiocarcinoma (CCA). Despite recent advances in the treatment of cancers, the 5-year survival rate for CCA patients currently remains poor, primarily due to early local invasion and distant metastasis of the cancer. This study aimed to investigate miR-200a expression in combined hepatolithiasis and CCA as well as its correlation with the clinical features of CCA. MATERIAL AND METHODS miR-200a expression in combined hepatolithiasis and CCA was detected by real-time reverse transcription PCR (qRT-PCR). Its correlation with the clinicopathology of CCA was analyzed by t-tests. The effect of miR-200a on the proliferation CCA cells was determined by MTT assay. The effect of miR-200a on the invasive ability of CCA cells was assessed by Boyden chamber test. RESULTS The expression level of MiR-200a in patients with combined hepatolithiasis and CCA was significantly decreased compared with patients with only hepatolithiasis (P<0.01). Furthermore, miR-200a expression in hepatic duct cancer RBE cells was substantially reduced compared with hepatolithiasis group (P<0.01). Correlation analysis showed that abnormal expression of miR-200a was only associated with the differentiation degree and metastasis of CCA. MiR-200a transfection significantly inhibited the proliferation and invasion of REB cells (P<0.01). CONCLUSIONS MiR-200a may suppress the proliferative and invasive ability of REB cells. The reduced miR-200a expression might be correlated with the development and progression of CCA.

[Expression of TPX2 in hepatocellular carcinoma and its clinical significance].

OBJECTIVE: To explore the expression of TPX2 and its significance in hepatocellular carcinoma (HCC) tissue and examine the relationship between TPX2 and clinicopathological characteristics of HCC. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical staining were used to compare the expression of TPX2 in tumor and adjacent non-tumoral tissues. RESULTS: The TPX2 mRNA expression was higher in tumor tissues than that in non-tumoral counterparts (30/50) (P < 0.05). The positive rate of TPX2 protein in tumor tissues was significantly higher than that in non-tumoral counterparts (56.0% vs 16.0%) (P < 0.05). The expression of TPX2 mRNA and protein were correlated with metastasis, recurrence and time of recurrence after curative resection (P < 0.05). CONCLUSION: An over-expression of TPX2 may be risk factor of metastasis and recurrence after curative resection so that it is a potential biomarker for early diagnosis and prognosis of HCC.

[The preliminary study on the function of methylenetetrahydrofolate dehydrogenase 2 in hepatocellular carcinoma].

OBJECTIVE: To investigate the expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in hepatocellular carcinoma (HCC) tissues and its correlation with clinical parameters. METHOD: Fluorogenic quantitative-polymerase chain reaction (FQ-PCR) was used to measure the MTHFD2 mRNA expression. The MTHFD2 protein expression was detected by immunohistochemical staining in cancerous tissues and adjacent noncancerous counterparts. The relationship of MTHFD2 expression, clinicopathological parameters and the prognosis of hepatocellular carcinoma was subsequently analysed. RESULTS: The MTHFD2 mRNA expression in cancerous tissues was higher than that in adjacent noncancerous counterparts (31/47) (P<0.05). The positive rate of MTHFD2 protein in cancerous tissues was significantly higher than that in adjacent noncancerous counterparts (69.5% vs. 33.9%) (P<0.05). MTHFD2 overexpression was found to correlate with clinical pathological parameters such as tumor metastasis, recurrence and poor prognosis (P<0.05). The patients with overexpressed MTHFD2 had shorter tumor-free survival time. CONCLUSIONS: Overexpression of MTHFD2 in HCC may be a risk factor of tumor metastasis and recurrence. MTHFD2 could be a new biomarker for prognosis of HCC.

[Expression of novel metastasis-promoting gene 1 and its clinical significance in hepatocellular carcinoma].

OBJECTIVE: To explore the expression of NVM-1(novel metastasis-promoting gene 1) in hepatocellular carcinoma (HCC) tissue and examine its clinical significance. METHODS: The expression of NVM-1 in 92 cases of HCC tumor tissues and non-tumor tissues was detected by immunohistochemical staining with SP (streptavidin-perosidase). And its clinical significance was evaluated. RESULTS: The staining of NVM-1 was predominantly located in the nucleus of HCC tumor tissue. The positive rate of NVM-1 was 52.2% in all detected cancers and it was higher than that in control non-tumor tissues (28.3%) and benign hepatic lesions (0) . A significant difference of positive rates existed between tumor and non-tumor tissues (P < 0.05). The expression of NVM-1 in HCC was not correlated with hepatic B virus (HBV), size, amount or cirrhosis, etc. However, it was correlated with TNM (P = 0.016), BCLC stage (P = 0.015), poor differentiation (P = 0.000), intrahepatic metastasis (P = 0.002), portal vein tumor thrombus (P = 0.023) and recurrence (P = 0.001). By Kaplan-Meier analysis, the median tumor-free survival time was 5 months in positive expression group and it was significantly shorter than 13 months in negative expression group (P = 0.001). CONCLUSION: There is probably a close relation between recurrence and metastasis and the expression of NVM-1 in HCC.

Achieving highly efficient 2D SnC monolayer-based photocatalyst for water splitting via a synergistic strategy of S-scheme heterostructure construction and silicon doping.

Owing to its stable graphene-like honeycomb structure, suitable band gap, and nontoxicity, SnC monolayer (ML) has attracted increasing attention in photocatalytic applications. One pertinent obstacle inherent to SnC ML-based photocatalysts has been the high energy barrier in hydrogen evolution reaction (HER) that always requires external energy input and/or strongly acidic conditions. Herein, we propose a two-dimensional (2D) SnC/ZrS2 van der Waals heterostructure (vdWHS) for highly efficient photocatalytic water splitting using first-principles calculations. The results show that the pristine vdWHS is an S-scheme heterostructure that works in acidic conditions for water splitting owing to the high energy barrier in HER. Notably, detailed further investigations show that doping Si in the SnC ML of the vdWHS can solve this high barrier problem, leading to a high-performance low-cost photocatalyst. Our work offers a convenient strategy to solve the notorious high barrier problem in HER that often troubles the SnC ML and other 2D materials such as transition metal dichalcogenide MLs for the design and fabrication of highly efficient photocatalysts.

Survival benefit of liver resection following complete response to transarterial chemoembolization for intermediate-stage hepatocellular carcinoma: a retrospective, multicenter, cohort study.

BACKGROUND: High rate of tumor recurrence jeopardized the long-term survival of hepatocellular carcinoma (HCC) patients with complete response to transarterial chemoembolization (TACE). This study aims to evaluate the survival benefit of liver resection (LR) following the complete response to TACE for intermediate-stage HCC. METHODS: A total of 281 intermediate-stage HCC patients with complete response to TACE followed by persistent observation (TACE group) or LR (TLR group) from 01 January 2011 to 31 December 2021 from three institutions in China were included. Overall survival (OS) and disease-free survival (DFS) of patients were compared between the two groups by propensity score-matching (PSM). RESULTS: After PSM, the 1-year, 3-year, and 5-year OS rates were 91.4, 71.5, and 57.1% in the TACE group, and 96.6, 81.8, and 72.1% in the TLR group. The 1-year, 3-year, and 5-year DFS rates were 50.6, 22.6, and 6.8% in the TACE group, and 77.3, 56.3, and 38.7% in the TLR group. Compared with the TACE group, the TLR group showed significantly longer OS (HR, 0.528; 95% CI: 0.315-0.887; P =0.014) and DFS (HR, 0.388; 95% CI: 0.260-0.580; P <0.001). In patients beyond up-to-seven criterion, no difference was observed with OS (HR, 0.708; 95% CI: 0.354-1.419; P =0.329). LR following the complete response to TACE was safety. CONCLUSIONS: This study suggests that intermediate-stage HCC patients could benefit from LR following the complete response to TACE, resulting in longer OS and DFS. In addition, patients beyond up-to-seven could not benefit from the LR treatments.

USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition.

Ripretinib, a broad-spectrum inhibitor of the KIT and PDGFRA receptor tyrosine kinases, is designated as a fourth-line treatment for gastrointestinal stromal tumor (GIST). It is tailored for patients resistant to imatinib, sunitinib, and regorafenib. As its increasing use, instances of resistance to ripretinib are becoming more frequent. Unfortunately, there are currently no scientifically mature treatment options available for patients resistant to ripretinib. Posttranslational modifications (PTMs) such as ubiquitination, in conjunction with its interplay with other modifications, play a collective role in regulating tumor initiation and progression. However, the specific association between ubiquitination and ripretinib resistance is not reported. Through proteome-ubiquitinome sequencing, increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected. Subsequent examination of the mass spectrometry findings validated the interaction through which TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST. Moreover, ZDHHC18 can palmitoylate MDH2, preventing its ubiquitination and further increasing its protein stability. The research underscores the correlation between posttranslational modifications, specifically ubiquitination, and drug resistance, emphasizing the potential of targeting the USP5-MDH2 axis to counteract ripretinib resistance in GIST.