Factor For Hepatocellular Carcinoma Research Articles

RETRACTED ARTICLE: lncRNA TINCR sponges miR-214-5p to upregulate ROCK1 in hepatocellular carcinoma

BackgroundOur preliminary bioinformatics analysis showed that lncRNA TINCR may absorb miR-214-5p by serving is sponge, while miR-214-5p targets ROCK1. This study aimed to investigate the interactions among these 3 factors in hepatocellular carcinoma (HCC).MethodsExpression of TINCR, ROCK1 and miR-214-5p in HCC and non-tumor tissues was detected by performing qPCR. The correlations among TINCR, ROCK1 and miR-214-5p in HCC tissues were analyzed by performing linear regression. Overexpression experiments were performed to analyze gene interactions. Cell proliferation was analyzed by CCK-8 assay.ResultsWe found that TINCR and ROCK1 were upregulated, while miR-214-5p was downregulated in HCC. TINCR and ROCK1 were positively correlated, while TINCR and miR-214-5p were not significantly correlated. In HCC cells, TINCR overexpression is followed by ROCK1 overexpression, while miR-214-5p overexpression induced the downregulation of ROCK1. In addition, TINCR and miR-214-5p did not affect the expression of each other. TINCR and ROCK1 overexpression led to increased rate of cancer cell proliferation, while miR-214-5p played an opposite role and reduced the effects of TINCR overexpression. Therefore, TINCR sponges miR-214-5p to upregulate ROCK1 in HCC, thereby promoting cancer cell invasion and migration.

Retinal dehydrogenase 5 (RHD5) attenuates metastasis via regulating HIPPO/YAP signaling pathway in Hepatocellular Carcinoma.

Retinal dehydrogenase 5 (RDH5) is an important enzyme in the visual cycle. Several studies have reported that the RDH family may play crucial roles in tumor prognosis. However, the role of RDH5 in tumor prognosis is still unclear. We examined the mRNA level of RDH5 by using q-PCR in hepatocellular carcinoma (HCC) and adjacent non-cancerous tissues. The proliferation rate of HCC cells was detected by MTS assay, and the invasive ability was examined by transwell and scratch wound assays. The YAP protein localization and expression were visualized by immunofluorescence in two different cell lines. CpG islands in the promoter region were predicted by using the methprimer database. Clinical characteristics of a patient cohort data came from The Cancer Genome Atlas database. RDH5 was significantly downregulated in hepatocellular carcinoma tissues, and low RDH5 expression was associated with metastasis and poor patient prognosis. Functional assays revealed that the RDH5 promoter is methylated in HCC cell lines. Moreover, overexpressing RDH5 can suppress metastasis by reversing the epithelial-mesenchymal transition (EMT) process, and RDH5 also inhibits cell proliferation in HCC cell lines. Furthermore, suppressing RDH5 can activate the Hippo/YAP signaling pathway and promote the nuclear translocation of YAP. Clinical data demonstrated that RDH5 is an independent prognostic factor in HCC. In our study, we provided the first evidence that RDH5 plays a crucial role in suppressing proliferation and metastasis, and the RDH5 promoter is methylated in hepatocellular carcinoma. And as an important regulator, RDH5 can suppress the Hippo/YAP signaling pathway. Taken together, it revealed that RDH5 might be a potential therapeutic target in HCC patients.

Predictive value of hypoxia, metabolism and immune factors for prognosis in hepatocellular carcinoma: a retrospective analysis and multicenter validation study.

The tumor microenvironment (TME), as a potent and pervasive factor of tumorigenesis and tumor progression, has a profound impact on the clinical outcomes of hepatocellular carcinoma (HCC). A systematic analysis of TME factors in HCC is still lacking and urgently needed. In this retrospective analysis and multicenter validation study, a total of 987 HCC patients with RNA-seq or microarray data and the corresponding clinical information from five cohorts were included. A TME risk score was developed based on five factors (hypoxia, nucleotide, TCA cycle, T helper cells and activated CD8 T cells). We also identified various types of clinical parameters and molecular features associated with the TME risk score. The TME risk factor network depicts close associations among the factors. Our TME risk score could be a practical and reliable predictor that can stratify patients according to distinct clinical outcomes and was validated by integrating five HCC patient cohorts (HR= 2.27, 95% CI: 1.79-2.86, P<0.001). Pan-cancer analysis also suggested that the prognostic signature was an effective prognostic indicator in 9,122 patients across 30 types of cancer. Correlation analysis revealed that the TME risk score was significantly associated with tumor progression-related clinical factors and molecular factors. TME factors are perturbations in HCC patients, and these alterations are vital determinants of both clinical outcomes and biological characteristics. The TME risk score we proposed is valuable for deciphering the molecular characteristics of the TME in HCC and is an effective prognostic predictor for HCC prognosis evaluation.

Overexpression of Ubiquitin-Specific Protease15 (USP15) Promotes Tumor Growth and Inhibits Apoptosis and Correlated With Poor Disease-Free Survival in Hepatocellular Carcinoma.

USP15 is a member of ubiquitin-specific proteases (USPs, the largest subfamily of deubiquitinases) and functions as a stabilize factor of target proteins in reversible ubiquitiantion progression. Dysregulated expression of USP15 has been observed in various cancers. However the expression profile and regulatory mechanism of USP15 in hepatocellular carcinoma (HCC) remains largely elusive. To exam the USP15 expression changes in the progression of HCC, we performed IHC analysis to test USP15 expression in a series of cancer-prone diseases including 2 normal liver tissues, 6 liver cirrhosis, 16 primary liver lesions and 15 metastases of hepatocellular carcinoma. The expression of USP15 was upregulated in various liver diseases in compared with normal tissue significantly (p < 0.05). Although no significant different of USP15 expression were discovered between cirrhotic tissue and primary tissue, its expression in HCC metastatic tissue was upregulated. Subsequently, we test the USP15 expression profile in a cohort of 66 HCC patients. USP15 expression was positively correlated with the recurrence of HCC significantly (p = 0.004). HCC patients with high USP15 expression had shorter disease free survival time in compare with those with low USP15 expression (56.9% VS 26.7%, P = 0.012). Subsequently, Cox multivariate analyses of clinical factors associated with disease free survival were performed and USP15 expression (p = 0.008) together with tumor size (p = 0.034) were proved to be independent predict factors in HCC. Then, we silenced USP15 expression in HCC cells and the results showed that downregulated USP15 expression resulting proliferation inhibition and apoptosis induction. In conclusion, our results suppose USP15 to be a potential target in HCC.

Hepatocellular carcinoma with initial presentation as metastatic spinal cord compression

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. The burden of HCC is highest in the sub-Saharan Africa, South-East Asia and China. The recognized risk factors for HCC are chronic hepatitis B virus and hepatitis C virus infection, dietary aflatoxin, and alcoholic liver disease among others. HCC typically presents with symptoms related to the primary tumor; abdominal pain, weight loss, and abdominal swelling. Extrahepatic spread is present in up to 15% of patients with HCC at the time of diagnosis and may be the primary presentation. The most common site of extrahepatic metastasis by several authors is the lungs. Bone metastases in HCC are not as rare as previously reported and the most frequent site is the spine. Bone metastasis is mainly osteolytic and may result in pathologic fractures, hypercalcemia, and reduced quality of life. Spinal metastasis of HCC is recognized as a terminal stage of the disease and considerably worsens the prognosis. Presented is a case of a 35-year old man who came to the hospital primarily with metastatic spinal cord compression syndrome with paraplegia and was found to have advanced HCC. He succumbed to the disease within one month of presentation. While Pott's disease of the spine and metastatic prostatic tumor are the most common causes of nontraumatic myelopathy in sub-Saharan Africa, HCC should always be considered in the differential diagnosis of any patient with vertebral disease of uncertain origin.

Study of Serum Soluble Programmed Death Ligand 1 as a Prognostic Factor in Hepatocellular Carcinoma in Egyptian Patients.

The expression of programmed cell death ligands on tumor cells has a role in the suppression of antitumor immunity, resulting in tumor immune evasion. In this study, we evaluated the prognostic value of the soluble form of programmed death-ligand1 (sPD-L1) in Egyptian hepatocellular carcinoma (HCC) patients. This prospective cohort study was performed between November 2016 to November 2018 on 85 individuals (25 HCC patients, 25 HCC with vascular invasion and/or extrahepatic metastasis, 25 patients with liver cirrhosis, 10 healthy controls). The levels of sPD-L1 were determined in all subjects and compared in different groups and stages of cirrhosis and HCC. The association between sPD-L1 levels and overall survival (OS) was assessed. Significant statistical difference in sPD-L1 was detected between different study groups. The cut-off value for normal sPD-L1 was defined by high sPD-L1 levels determined in a healthy control cohort. It was 2.522 ng/ml. In HCC patients, cut-off value was 7.42 ng/ml (sensitivity 88%, specificity 100%). In HCC with vascular invasion or metastasis, cut-off value was 9.62 ng/ml (sensitivity 88%, specificity 88%). Patients with high serum sPD-L1 or serum bilirubin concentrations had an increased risk of mortality. High sPD-L1 level could be a possible prognostic indicator for a poor outcome in liver cirrhosis and HCC patients. The predictive value of sPD-L1 levels for a successful anti- PD1/PD-L1 therapy should be investigated in the future.

Impact of Direct Acting Antivirals on Survival in Patients with Chronic Hepatitis C and Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) represents a global public health burden, affecting an estimated 14 million persons worldwide, and is the third leading cause of cancer mortality. Within the United States, HCC is ranked 7th for cancer related mortality and has seen a doubling in incidence from 1975 to 2007. The primary predisposing factors for HCC carcinogenesis is liver cirrhosis. Cirrhosis risk factors include chronic alcohol use, viral hepatitis, including hepatitis c (HCV), and non-alcoholic fatty liver disease. Chronic HCV infection is the second most common risk factor for HCC and is responsible for 10–25% of all HCC cases. Over 20–30 years, 20–30% of patients with chronic HCV infections will develop cirrhosis and end stage liver disease and 1–4% of these patients will progress to HCC each year. Of all HCV related HCC cases, 80–90% occur in the setting of cirrhosis. With more than 3.5 million HCC patients in the United States and an estimated 130–170 million patients worldwide currently infected with HCV, the importance of HCV management in HCC therapeutic care and prevention is clear. The major current therapeutic goal for HCV and prevention of liver disease progression is sustained viral response (SVR), which is defined by negative HCV RNA at 12 weeks post-treatment (SVR12) and appears to be durable with a late virologic relapse rate of less than 1%. Therapeutic management of HCV has recently shifted from interferon-based therapies to all-oral interferon-free direct-acting antiviral (DAA) combination regimens. DAAs are a new class of drugs that target nonstructural proteins responsible for replication and infection of the hepatitis c virus. Genotype specific DAA therapies have been shown to reach SVR12 exceeding 90% of patients with fewer adverse effects compared with historic interferon-based regiments. SVR12 from DAA regimens have been associated with a decrease in liver outcomes including cirrhosis, hepatic decompensation, HCC and mortality. However, the impact of DAA regimens on clinical outcomes in patients with HCC remain limited. This study evaluates the impact of DAA on overall survival in HCV patients with HCC with the a priori hypothesis that SVR12 would be associated with improved outcome.

FIBCD1 overexpression predicts poor prognosis in patients with hepatocellular carcinoma.

Fibrinogen C domain-containing 1 (FIBCD1) is an acetyl-recognition receptor that affects the occurrence and development of certain tumors. However, the prognostic significance of FIBCD1 in hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore FIBCD1 expression in HCC and to determine the prognostic value of FIBCD1 in patients with HCC. A total of 1,058 liver tissue samples with detailed and complete clinical information were collected, including 495 HCC samples. Tissue microarray immunohistochemistry analysis was used to evaluate FIBCD1 protein expression in the collected tissues. The Kaplan-Meier plotter online tool was used to investigate the association between FIBCD1 expression and prognosis of patients with HCC. Oncomine and the Gene Expression Profiling Interactive Analysis database were used for bioinformatics analysis of FIBCD1. Results showed that FIBCD1 expression was higher in HCC and was associated with tumor diameter (P=0.002), tumor number (P=0.001), tumor node metastasis stage (P<0.001), primary tumor (T; P<0.001), lymph node metastases (N; P=0.002), distant metastases (M; P=0.023), differentiation degree (P=0.003), vascular invasion (P<0.001) and liver cirrhosis (P=0.011). Patients with HCC and high FIBCD1 expression had worse overall survival than those with low FIBCD1 expression. High FIBCD1 expression (P<0.001), TNM stage (P=0.003), T (P<0.001), N (P=0.014), and vascular invasion (P<0.001) were independent prognostic factors in HCC. Hence, FIBCD1 may be a novel biomarker for prognosis evaluation of HCC.

S100A14 protein as diagnostic and prognostic marker in hepatocellular carcinoma

BackgroundProtein S100A14 has recently been implicated in the progress of several types of cancers. This study aimed to investigate the clinical significance of S100A14 in the diagnosis of hepatocellular carcinoma (HCC).ResultsS100A14 was significantly elevated in the HCC group. A cut-off value for serum S100A14 between the HCC group and cirrhosis group is > 0.47 with a sensitivity of 100% and specificity of 88.57%. S100A14 level was a significant diagnostic factor for HCC and a good reference for HCC progression.ConclusionThese results suggest that S100A14 is a good diagnostic marker for HCC.

IL-17 promotes hepatocellular carcinoma through inhibiting apoptosis induced by IFN-γ

Interleukin-17 (IL-17) and interferon-γ (IFN-γ), two inflammatory cytokines, are present in cancerous liver tissues. IL-17 was recently identified as an oncogenic factor in hepatocellular carcinoma (HCC), but its underlying mechanisms are largely obscure. Here, we aimed to investigate the interaction between IL-17 and IFN-γ and its influence on HCC cell apoptosis and growth in vitro and in vivo. We found that the expression of IL-17, but not IFN-γ, was obviously increased in HCC tissues. Higher IL-17 expression in tumor tissues correlated with shorter survival times. IFN-γ apparently increased apoptosis of HCC cells. IL-17 alone had no effect on apoptosis of HCC cells but reversed apoptosis induced by IFN-γ. IFN-γ mildly promoted the expression of protein inhibitor of activated signal transducer and activators of transcription 1 (PIAS1) and the activation of NF-κB, and these effects were greatly enhanced when combined with IL-17. PIAS1 silencing not only further amplified apoptosis induced by IFN-γ alone but also abolished the inhibitory effects of IL-17 on IFN-γ-induced apoptosis in HCC cells. An NF-κB inhibitor obviously decreased the upregulated expression of PIAS1 induced by IFN-γ plus IL-17 and IFN-γ alone. IFN-γ treatment retarded the tumor growth of HCC cells in an in vivo xenograft tumor model, which could be largely inhibited by combined treatment with IL-17. In conclusion, IL-17 obviously inhibits the antitumor effects of IFN-γ in hepatoma cells and, in turn, accelerates HCC development through upregulating the expression of the negative feedback regulator PIAS1 of the JAK/STAT1 pathway via enhancing activation of NF-κB.

An Association Between Platelet Count and Hepatocellular Carcinoma Overall Survival: A Secondary Analysis

Background: Recent evidence shows that platelets act as critical factors in hepatocellular carcinoma (HCC) proliferation1 and contribute to the distant metastasis. Platelet count(PLT) has been proved as an essential biomarker for HCC development. However, the nonlinear relationship between PLT and HCC overall survival is still unclear. Methods: Cox proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs for HCC. The nonlinear relationship was estimated through a restricted cubic spline regression, and a two-piece-wise Cox proportional hazards model was further performed to calculate the threshold effect. We used multiple imputation to deal with the missing data. Findings: A total of 971 newly diagnosed HCC patients with Barcelona clinic liver cancer stage B were identified for the secondary analysis. In the multivariate analysis, Log PLT was associated with an 88% risk increase of death(HR, 1.88;1.27 to 2.80) with adjustment for gender, Child-Pugh class, age X diameter of main tumour, both lobe with lesions X No. of the intrahepatic lesions, AFP( 10.83 after adjusting for potential confounders. The core results were consistent with those from the sensitivity analysis. Besides, a significantly higher hazard risk was found in the patients with age 50 mm, Hgb≥120 g/L and CRP>10 mg/L. Conclusion: Platelet count was nonlinearly associated with hepatocellular carcinoma overall survival. Funding Statement: This research received financial support from the National Natural Science Foundation of China (Nos 81502360); the Natural Science Foundation of Fujian Province (Nos 2018J01352 and 2016J01576 and 2016J01586); the Science and Technology Innovation Joint Foundation of Fujian Province(Nos 2017Y9125). Declaration of Interests: The authors state: None. Ethics Approval Statement: The Department approved this study protocol (2017-FXY-129) of Clinical Research of Sun Yat-sen University Cancer Center. Because this was a secondary analysis study, and the data were anonymous, the requirement for informed consent was waived.

Gene-environment interactions between GSTs polymorphisms and targeted epigenetic alterations in hepatocellular carcinoma following organochlorine pesticides (OCPs) exposure

Exposure to environmental pollutant organochlorine pesticides (OCPs) and the role of tumour suppressor GSTs gene polymorphisms as well as epigenetic alterations have all been well reported in hepatocarcinogenesis. However, the interplay between environmental risk factors and polymorphic tumour suppressor genes or epigenetic factors in hepatocellular carcinoma (HCC) development remains ambiguous. Herein, we investigated the relationship of three GSTs polymorphisms (GSTT1 deletion, GSTM1 deletion, GSTP1 rs1695) as well as GSTP1 promoter region DNA methylation and HCC risk with a particular focus on the interaction with OCPs exposure among 90 HCC cases and 99 controls in a Chinese population. Serum samples were analysed for OCPs exposure employing gas chromatography coupled with mass selective detector (GC-MS). GSTs polymorphisms and epigenetic alterations were determined using high-resolution melting PCR (HRM PCR) and DNA sequencing. After adjusting for confounders (HBV infection, smoking, alcohol consumption, BMI, age, gender), OCPs exposure and GSTP1 methylation is significantly associated with elevated risk of HCC, while no significance is observed for GSTs polymorphisms. Moreover, the effects of OCPs exposure on HCC risk are more pronounced amongst GSTP1 (Ile/Val + Val/Val) and GSTP1 promoter methylation subjects than those who were GSTP1 (Ile/Ile) and unmethylated subjects. The interactions between OCPs exposure and GSTP1 genotype as well as GSTP1 epigenetic status are statistically significant. The current study demonstrates the importance of gene-environment interactions in the multifactorial development of HCC.

Hypoxia‑inducible factors in hepatocellular carcinoma (Review).

Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia-inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.

C-Myc transactivates GP73 and promotes metastasis of hepatocellular carcinoma cells through GP73-mediated MMP-7 trafficking in a mildly hypoxic microenvironment

Golgi phosphoprotein 73 (GP73), encoded by GOLM1, is a highly expressed factor in hepatocellular carcinoma (HCC) cells and has been regarded for several years as a remarkable serum biomarker for the diagnosis of HCC. Recently, it was found that upregulation of GP73 promotes cancer metastasis, but the mechanism is complex, and it is even unclear how the gene is transactivated in HCC cells. In this study, it was discovered that c-Myc transactivated GP73 in a mildly hypoxic microenvironment and that the activation of c-Myc upregulated the expression of matrix metalloproteinase-7 (MMP-7). Moreover, it is shown that GP73 interacted with intracellular MMP-7 in the region of the cytoplasmic domain and facilitated the trafficking and secretion of MMP-7, resulting in cell metastasis. This study indicates that GP73 is transactivated by c-Myc and serves as a transporter in the trafficking of intracellular MMP-7 in HCC cells. These findings suggest that GP73 is a potential target for combating metastatic HCC.

Nucleolar spindle associated protein 1 (NUSAP1) facilitates proliferation of hepatocellular carcinoma cells

Background: The most fundamental characteristic of cancer cells is abnormal proliferation, which is partly due to deregulation of cell cycle. Nucleolar spindle associated protein 1 (NUSAP1) is originally identified as microtubule and chromosome binding protein and takes an important role in chromosome segregation fidelity. Recent studies have been documented that NUSAP1 is associated with the progression of several cancers. However, its expressions and functions are unclear in hepatocellular carcinoma (HCC). Methods: qPCR and western blotting were used to examine NUSAP1 levels in fresh paired HCC tissues and corresponding adjacent normal liver tissues (ANT). MTT and colony formation assay were performed to evaluate whether NUSAP1 can influence the proliferation of HCC cells. Anchorage-independent growth assay was implemented to detect the effect of NUSAP1 on in vitro tumorigenicity capacity. Flow cytometry, qPCR and western blotting assay were used to clarify the detailed mechanisms that NUSAP1 accelerates the capability for cell proliferation and in vitro tumorigenicity. Results: Firstly, we analyzed the availably public dataset The Cancer Genome Atlas (TCGA), and discovered that NUSAP1 is dramatically upregulated in HCC tissues and closely correlated with poor prognosis of patients suffering HCC, which was confirmed in fresh HCC tissues and ANT. Subsequently, cell function assay illustrated that the upregulation of NUSAP1 facilitates proliferation and in vitro tumorigenicity capacity of HCC cells. Besides, molecular experiments suggested that NUSAP1 promotes cell cycle transition of HCC cells. Conclusions: In summary, the above results inferred that NUSAP1 takes an indispensable role in cell cycle progression. And it might be served as a novel prognostic factor in HCC.

A Novel Index in Hepatocellular Carcinoma Patients After Curative Hepatectomy: Albumin to Gamma-Glutamyltransferase Ratio (AGR).

Aim: As high gamma-glutamyltransferase level or low albumin had negative impacts on the prognosis of hepatocellular carcinoma (HCC), the prognostic role of albumin to gamma-glutamyltransferase ratio (AGR) in HCC patients after hepatectomy remains unclear.Methods: Between January 2007 and December 2015, 1143 HCC patients after hepatectomy were reviewed from a prospectively maintained database in West China Hospital. All qualified patients (n = 959) were classified as training set (year 2007–2012, n = 480) and validation set (year 2012–2017, n = 479). A time-dependent receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance.Result: AGR = 0.5 was identified as the best cut-off point to predict recurrence free survival (RFS) and overall survival (OS) in the training set. Low AGR was related to poor tumor characteristics and high systemic inflammation. Based on the multivariate analysis, high AGR was an independent predictor for better RFS and OS with an hazard ratio of 0.696 and 0.673. The high AGR group had better RFS and OS than the low AGR group in the training set as well as the validation set. The AGR-based score (AGR-PLR) could stratify HCC patients into three subgroups with different prognosis in the training and validation set. Patients with score 1 had a worse prognosis than those with AGR-PLR score 0, but better than those with AGR-PLR score 2. The predictive accuracy of the AGR-PLR score appeared superior to that of the AGR or PLR alone.Conclusions: we firstly reported that AGR ≤ 0.5 was an independently prognostic factor in HCC after hepatectomy. The AGR-PLR score could further improve the discriminatory ability of prognosis.

Nucleolar spindle associated protein 1 (NUSAP1) facilitates proliferation of hepatocellular carcinoma cells.

BackgroundThe most fundamental characteristic of cancer cells is abnormal proliferation, which is partly due to deregulation of cell cycle. Nucleolar spindle associated protein 1 (NUSAP1) is originally identified as microtubule and chromosome binding protein and takes an important role in chromosome segregation fidelity. Recent studies have been documented that NUSAP1 is associated with the progression of several cancers. However, its expressions and functions are unclear in hepatocellular carcinoma (HCC).MethodsqPCR and western blotting were used to examine NUSAP1 levels in fresh paired HCC tissues and corresponding adjacent normal liver tissues (ANT). MTT and colony formation assay were performed to evaluate whether NUSAP1 can influence the proliferation of HCC cells. Anchorage-independent growth assay was implemented to detect the effect of NUSAP1 on in vitro tumorigenicity capacity. Flow cytometry, qPCR and western blotting assay were used to clarify the detailed mechanisms that NUSAP1 accelerates the capability for cell proliferation and in vitro tumorigenicity.ResultsFirstly, we analyzed the availably public dataset The Cancer Genome Atlas (TCGA), and discovered that NUSAP1 is dramatically upregulated in HCC tissues and closely correlated with poor prognosis of patients suffering HCC, which was confirmed in fresh HCC tissues and ANT. Subsequently, cell function assay illustrated that the upregulation of NUSAP1 facilitates proliferation and in vitro tumorigenicity capacity of HCC cells. Besides, molecular experiments suggested that NUSAP1 promotes cell cycle transition of HCC cells.ConclusionsIn summary, the above results inferred that NUSAP1 takes an indispensable role in cell cycle progression. And it might be served as a novel prognostic factor in HCC.

SOCS1 Blocks G1-S Transition in Hepatocellular Carcinoma by Reducing the Stability of the CyclinD1/CDK4 Complex in the Nucleus

Background: Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the use of this type of drug alone is often ineffective and elicits adverse side effects. The development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. Methods: We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. The molecular mechanism of SOCS1 regulating cell proliferation was proved through transcriptome sequencing, western blot and Co-IP. Findings: When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21 and P27, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. Interpretation: As a tumour inhibitory factor in HCC, SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors. Funding Statement: Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No.91542205), National S&T Major Project (No. 2017ZX10203205), Zhejiang International Science and Technology Cooperation Project (No.2016C04003), National Natural Science Foundation of China (No. 81773070). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocol was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University. All experiments containing animals according to protocols approved by Animal Care and Use Committee of Zhejiang University.

Platelets as Key Factors in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in the setting of chronic inflammation and liver damage. The hepatic microenvironment plays a crucial role in the disease development, as players such as hepatic stellate cells, resident liver macrophages (Kupffer cells), endothelial cells, extracellular matrix, and a variety of immune cells interact in highly complex and intertwined signaling pathways. A key factor in these cross-talks are platelets, whose role in cancer has gained growing evidence in recent years. Platelets have been reported to promote HCC cell proliferation and invasion, but their involvement goes beyond the direct effect on tumor cells, as they are known to play a role in pro-fibrinogenic signaling and the hepatic immune response, as well as in mediating interactions between these factors in the stroma. Anti-platelet therapy has been shown to ameliorate liver injury and improve the disease outcome. However, platelets have also been shown to play a crucial role in liver regeneration after organ damage. Therefore, the timing and microenvironmental setting need to be kept in mind when assessing the potential effect and therapeutic value of platelets in the disease progression, while further studies are needed for understanding the role of platelets in patients with HCC.

Elevated Mortalin correlates with poor outcome in hepatocellular carcinoma

Although several lines of evidence existed suggesting that Mortalin was linked with survival in malignant tumors; it has been barely described regarding the prognostic involvement of its expression in hepatocellular carcinoma (HCC). Herein, to understand the prognostic meaning of Mortalin expression, Immunohistochemistry was undertaken to observe the immunohistochemical characteristics of Mortalin on HCC tissue microarray consisting of 90 cases of HCC and its paired normal control dots, followed by detailed statistical analysis with the accompanying clinicopathological variables available, including gender, age, tumor size, differentiation, cirrhosis, vascular invasion, clinical stage, T classification and intrahepatic metastases. Meanwhile, Kaplan-Meier survival curve was plotted to analyze the prognostic difference for patients with high and low expression of Mortalin. It was exhibited that Mortalin was over-expressed in HCC tissues relative to paired normal control and elevated Mortalin significantly correlated with vascular invasion, clinical stage and intrahepatic metastasis. Kaplan-Meier survival analysis revealed that Mortalin was remarkably associated with overall survival and disease-free survival. Multivariate Cox regression analysis showed that expression of Mortalin was an independent prognostic factor in HCC. Collectively, the data we provided here support the prognostic prediction value of Mortalin in HCC.