|
1
|
Le HDM, Vo DT, Do HT, Le HNG, Phan CC, Nguyen DT, Le QND. Hepatectomy in a young patient with advanced hepatocellular carcinoma and poor prognostic imaging features: A case of recurrence-free survival. Radiol Case Rep 2025; 20:2704-2709. [PMID: 40151292 PMCID: PMC11937630 DOI: 10.1016/j.radcr.2025.02.085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/29/2025] Open
Abstract
A 45-year-old male with chronic hepatitis B presented with an advanced hepatocellular carcinoma (HCC) occupying the entire left liver and invading the left portal vein. Despite multiple poor prognostic imaging features, including vascular invasion, corona enhancement, an incomplete capsule, intratumoral necrosis, intratumoral arteries, and irregular tumor borders, the patient elected to undergo a left hepatectomy. Although Barcelona Clinic Liver Cancer (BCLC) staging classified the case as stage C, a resection was successfully performed. Remarkably, 6 years postsurgery, the patient remains recurrence-free. This report highlights a rare, fortunate outcome in a high-risk HCC case and underscores the potential of surgical intervention even in advanced HCC.
Collapse
Affiliation(s)
- Huyen Duy Mai Le
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
| | - Duc Tan Vo
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
- Department of Diagnostic Imaging, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Hai Trong Do
- Department of General Surgery, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
| | - Hy Nguyen Gia Le
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
| | - Chien Cong Phan
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
| | - Duy Thanh Nguyen
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
| | - Quynh Nguyen Diem Le
- Department of Diagnostic Imaging, University Medical Center, Ho Chi Minh City, Vietnam
| |
Collapse
|
|
2
|
Yan J, Liao Q, Xie Y, Chen S. CCL26 as a prognostic biomarker in hepatocellular carcinoma: integrating bioinformatics analysis, clinical validation, and radiomics score. Discov Oncol 2025; 16:502. [PMID: 40205283 PMCID: PMC11981991 DOI: 10.1007/s12672-025-02280-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND CCL26 has been identified as a potential prognostic biomarker in hepatocellular carcinoma (HCC). This study aimed to assess the prognostic significance of CCL26 and develop a radiomics score (Rad-score) for predicting outcomes in HCC patients. METHODS Data from 316 HCC patients, including genomic information, computed tomography (CT) images, and clinicopathological data, were analyzed. The prognostic value of CCL26 was evaluated in 295 TCGA patients using Kaplan-Meier and Cox regression analyses, and validated in 21 patients from Jiujiang No. 1 People's Hospital. Gene set variation and immune cell infiltration analyses were conducted to elucidate the biological functions of CCL26. Radiomic models for predicting CCL26 expression were constructed using CT images and genomic data from 34 TCGA patients. Radiomic features were extracted from tumor regions and screened using maximum relevance minimum redundancy (mRMR) and recursive feature elimination (RFE). Two Rad-scores were generated via logistic regression and validated using internal fivefold cross-validation. A prognostic nomogram incorporating the optimal Rad-score, gender, and hepatic inflammation was developed using Cox proportional hazards regression. RESULTS Elevated CCL26 levels correlated with poor prognosis, as confirmed by immunohistochemistry. The optimal Rad-score, combined with gender and hepatic inflammation, accurately predicted overall survival (OS), with areas under the receiver operating characteristic curve (AUCs) of 0.819, 0.902, and 0.982 for 24-, 36-, and 48 month survival, respectively. Calibration curves and decision curve analysis (DCA) demonstrated the accuracy and clinical utility of the model. CONCLUSIONS CCL26 serves as a significant prognostic biomarker in HCC. The developed Rad-score provides an effective, non-invasive tool for predicting patient outcomes and enhancing clinical decision-making. This study not only highlights the prognostic role of CCL26 but also offers a novel approach for evaluating HCC patient prognosis through radiomics.
Collapse
Affiliation(s)
- Junjun Yan
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China
- Department of Gastroenterology, Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, 332000, China
| | - Qiangming Liao
- Department of Gastrointestinal Surgery, Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, 332000, China
| | - Yong Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China.
| | - Sihai Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China.
| |
Collapse
|
|
3
|
Imai K, Takai K, Unome S, Miwa T, Hanai T, Suetsugu A, Shimizu M. Lenvatinib Exacerbates the Decrease in Skeletal Muscle Mass in Patients with Hepatocellular Carcinoma, Whereas Atezolizumab Plus Bevacizumab Does Not. Cancers (Basel) 2024; 16:442. [PMID: 38275883 PMCID: PMC10814020 DOI: 10.3390/cancers16020442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/11/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
This study aimed to evaluate chronological changes in skeletal muscle index (SMI), subcutaneous and visceral adipose tissue indices (SATI and VATI), AFP, PIVKA-II, and ALBI scores during atezolizumab plus bevacizumab (AB) or lenvatinib (LEN) treatment for hepatocellular carcinoma (HCC) and the effect of these changes on survival. A total of 94 patients with HCC (37 were on AB and 57 on LEN) were enrolled. SMI, SATI, VATI, AFP, PIVKA-II, and ALBI scores were analyzed at the time of the treatment introduction (Intro), 3 months after the introduction (3M), at drug discontinuation (End), and the last observational time (Last). The differences between chronological changes were analyzed using the Wilcoxon paired test. The independent predictors for survival and the changes in SMI during AB or LEN (c-SMI%) were analyzed using the Cox proportional hazards model treating all these factors as time-varying covariates and the analysis of covariance, respectively. SMI in the AB group was maintained over time (42.9-44.0-40.6-44.2 cm2/m2), whereas that in the LEN group significantly decreased during the Intro-3M (p < 0.05) and 3M-End (p < 0.05) period (46.5-45.1-42.8-42.1 cm2/m2). SMI (p < 0.001) was an independent predictor for survival together with AFP (p = 0.004) and ALBI score (p < 0.001). Drug choice (AB or LEN; p = 0.038) and PIVKA-II (p < 0.001) were extracted as independent predictors for c-SMI%. AB treatment was significantly superior to LEN in terms of maintaining skeletal muscle, which is an independent predictor for survival.
Collapse
Affiliation(s)
- Kenji Imai
- Department of Gastroenterology/Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (K.T.); (S.U.); (T.H.); (A.S.); (M.S.)
| | | | | | | | | | | | | |
Collapse
|
|
4
|
Pelizzaro F, Trevisani F, Simeon V, Vitale A, Cillo U, Piscaglia F, Missale G, Sangiovanni A, Foschi FG, Cabibbo G, Caturelli E, Di Marco M, Azzaroli F, Brunetto MR, Raimondo G, Vidili G, Guarino M, Gasbarrini A, Campani C, Svegliati-Baroni G, Giannini EG, Mega A, Masotto A, Rapaccini GL, Magalotti D, Sacco R, Nardone G, Farinati F. Predictors of non-transplantable recurrence in hepatocellular carcinoma patients treated with frontline liver resection. Liver Int 2023; 43:2762-2775. [PMID: 37753540 DOI: 10.1111/liv.15719] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 08/09/2023] [Accepted: 08/21/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non-transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR. METHODS From the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up-to-seven criteria were compared between patients with HCC <4 and ≥4 cm. RESULTS During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up-to-seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence-free survival and overall survival. HCC size ≥4 cm and high alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up-to-seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non-transplantable recurrence. CONCLUSIONS Despite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long-term survival. Non-transplantable recurrence is predicted by HCC size and AFP levels, among pre-operatively available variables. High-risk patients could be considered for frontline LT or listed for transplantation even before recurrence.
Collapse
Affiliation(s)
- Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, Padova, Italy
| | - Franco Trevisani
- Unit of Semeiotics, Liver and Alcohol-related diseases, Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Vittorio Simeon
- Medical Statistics Unit, Mental, Physical Health and Preventive Medicine, University of Campania 'Luigi Vanvitelli', Napoli, Italy
| | - Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Hepatobiliary Surgery and Liver Transplantation Unit, Azienda Ospedale-Università di Padova, Padova, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Hepatobiliary Surgery and Liver Transplantation Unit, Azienda Ospedale-Università di Padova, Padova, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, Unit of Infectious Diseases and Hepatology, University of Parma, Parma, Italy
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesco G Foschi
- Department of Internal Medicine, Ospedale per gli Infermi di Faenza, Faenza, Italy
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | | | | | - Francesco Azzaroli
- Gastroenterology Unit, Department of Surgical and Medical Sciences, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maurizia R Brunetto
- Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine Unit, University of Pisa, Pisa, Italy
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, Clinical and Molecular Hepatology Unit, University of Messina, Messina, Italy
| | - Gianpaolo Vidili
- Department of Medicine Surgery and Pharmacy, Centralized Day Hospital of the medical area, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Diseases of the Liver and Biliary System Unit, University of Napoli 'Federico II', Napoli, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Firenze, Italy
| | | | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genova, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Andrea Mega
- Gastroenterology Unit, Bolzano Regional Hospital, Bolzano, Italy
| | - Alberto Masotto
- Gastroenterology Unit, Ospedale Sacro Cuore Don Calabria, Negrar, Italy
| | - Gian Ludovico Rapaccini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Donatella Magalotti
- Division of Internal Medicine, Neurovascular and Hepatometabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Italy
| | - Gerardo Nardone
- Department of Clinical Medicine and Surgery, Hepato-Gastroenterology Unit, University of Napoli 'Federico II', Napoli, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Gastroenterology Unit, Azienda Ospedale-Università di Padova, Padova, Italy
| |
Collapse
|
|
5
|
Wang XK, Guo YX, Wang M, Zhang XD, Liu ZY, Wang MS, Luo K, Huang S, Li RF. Identification and validation of candidate clinical signatures of apolipoprotein L isoforms in hepatocellular carcinoma. Sci Rep 2023; 13:20969. [PMID: 38017264 PMCID: PMC10684526 DOI: 10.1038/s41598-023-48366-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 11/25/2023] [Indexed: 11/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide with an increasing number of new cases each year. Apolipoprotein (APOL) isoforms have been explored for their associations with HCC.The GSE14520 cohort was used for training data; The Cancer Genome Atlas (TCGA) database was used for validated data. Diagnostic, prognostic significance and mechanisms were explored using these cohorts. Risk score models and nomograms were constructed using prognosis-related isoforms and clinical factors for survival prediction. Oncomine and HCCDB databases were further used for validation of diagnostic, prognostic significance. APOL1, 3, and 6 were differentially expressed in two cohorts (all P ≤ 0.05). APOL1 and APOL6 had diagnostic capacity whereas APOL3 and APOL6 had prognostic capacity in two cohorts (areas under curves [AUCs] > 0.7, P ≤ 0.05). Mechanism studies demonstrated that APOL3 and APOL6 might be involved in humoral chemokine signaling pathways (all P ≤ 0.05). Risk score models and nomograms were constructed and validated for survival prediction of HCC. Moreover, diagnostic values of APOL1 and weak APOL6 were validated in Oncomine database (AUC > 0.700, 0.694); prognostic values of APOL3 and APOL6 were validated in HCCDB database (all P < 0.05). Differentially expressed APOL1 and APOL6 might be diagnostic biomarkers; APOL3 and APOL6 might be prognostic biomarkers of RFS and OS for HCC via chemokine signaling pathways.
Collapse
Affiliation(s)
- Xiang-Kun Wang
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Yu-Xiang Guo
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Miao Wang
- Department of Gastrointestinal Oncology, Nanyang Second General Hospital, Nanyang, 473009, Henan Province, People's Republic of China
| | - Xu-Dong Zhang
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Zhong-Yuan Liu
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Mao-Sen Wang
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Kai Luo
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Shuai Huang
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Ren-Feng Li
- Departments of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan Province, People's Republic of China.
| |
Collapse
|
|
6
|
Zhang GX, Ding XS, Wang YL. Prognostic model of hepatocellular carcinoma based on cancer grade. World J Clin Cases 2023; 11:6383-6397. [PMID: 37900243 PMCID: PMC10600993 DOI: 10.12998/wjcc.v11.i27.6383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/02/2023] [Accepted: 08/23/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. With highly invasive biological characteristics and a lack of obvious clinical manifestations, HCC usually has a poor prognosis and ranks fourth in cancer mortality. The aetiology and exact molecular mechanism of primary HCC are still unclear. AIM To select the characteristic genes that are significantly associated with the prognosis of HCC patients and construct a prognosis model of this malignancy. METHODS By comparing the gene expression levels of patients with different cancer grades of HCC, we screened out differentially expressed genes associated with tumour grade. By protein-protein interaction (PPI) network analysis, we obtained the top 2 PPI networks and hub genes from these differentially expressed genes. By using least absolute shrinkage and selection operator Cox regression, 13 prognostic genes were selected for feature extraction, and a prognostic risk model of HCC was established. RESULTS The model had significant prognostic ability in HCC. We also analysed the biological functions of these prognostic genes. CONCLUSION By comparing the gene profiles of patients with different stages of HCC, We have constructed a prognosis model consisting of 13 genes that have important prognostic value. This model has good application value and can be explained clinically.
Collapse
Affiliation(s)
- Guo-Xin Zhang
- Department of General Surgery, Aviation General Hospital, Beijing 100010, China
| | - Xiao-Sheng Ding
- Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - You-Li Wang
- Department of General Surgery, Aviation General Hospital, Beijing 100010, China
| |
Collapse
|
|
7
|
Ye D, Ma J, Yu T, Ran F, Zha Y. LncRNA FAM13A-AS1, transcriptionally regulated by PHOX2B, modulates hepatocellular carcinoma chemoresistance via stabilizing PPARγ. Gene 2023:147570. [PMID: 37330023 DOI: 10.1016/j.gene.2023.147570] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Hepatocellular carcinoma (HCC) is a major global public health concern, with approximately 79 million new cases and 75 million HCC-related deaths occurring annually worldwide. Among the drugs, cisplatin (DDP) is considered a cornerstone and has been shown to significantly inhibit cancer progression. However, the mechanism underlying DDP-resistance in HCC remains unclear. This study aimed to identify a novel lncRNA. FAM13A Antisense RNA 1 (FAM13A-AS1), that promotes the proliferation of DDP-resistant HCC cells and to elucidate its downstream and upstream mechanisms in the progression of HCC DDP-resistance. Our results suggest that FAM13A-AS1 interacts directly with Peroxisome Proliferator Activated Receptor γ (PPARγ), stabilizing its protein through de-ubiquitination. Moreover, our findings indicate that Paired Like Homeobox 2B (PHOX2B) transcriptionally regulates the expression of FAM13A-AS1 in HCC cells. These results shed new light on the understanding of the progression of HCC DDP-resistance.
Collapse
Affiliation(s)
- Daowen Ye
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Jun Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Tingdong Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Fengming Ran
- Department of Pathology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| | - Yong Zha
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
| |
Collapse
|
|
8
|
Hu J, Gong N, Li D, Deng Y, Chen J, Luo D, Zhou W, Xu K. Identifying hepatocellular carcinoma patients with survival benefits from surgery combined with chemotherapy: based on machine learning model. World J Surg Oncol 2022; 20:377. [PMID: 36451200 PMCID: PMC9714169 DOI: 10.1186/s12957-022-02837-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 10/03/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is still fatal even after surgical resection. The purpose of this study was to analyze the prognostic factors of 5-year survival rate and to establish a model to identify HCC patients with gain of surgery combined with chemotherapy. METHODS All patients with HCC after surgery from January 2010 to December 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic analysis were used to analyze the prognostic factors of patients, and the risk prediction model of 5-year survival rate of HCC patients was established by classical decision tree method. Propensity score matching was used to eliminate the confounding factors of whether to receive chemotherapy in high-risk group or low-risk group. RESULTS One-thousand six-hundred twenty-five eligible HCC patients were included in the study. Marital status, α-fetoprotein (AFP), vascular infiltration, tumor size, number of lesions, and grade were independent prognostic factors affecting the 5-year survival rate of HCC patients. The area under the curve of the 5-year survival risk prediction model constructed from the above variables was 0.76, and the classification accuracy, precision, recall, and F1 scores were 0.752, 0.83, 0.842, and 0.836, respectively. High-risk patients classified according to the prediction model had better 5-year survival rate after chemotherapy, while there was no difference in 5-year survival rate between patients receiving chemotherapy and patients not receiving chemotherapy in the low-risk group. CONCLUSIONS The 5-year survival risk prediction model constructed in this study provides accurate survival prediction information. The high-risk patients determined according to the prediction model may benefit from the 5-year survival rate after combined chemotherapy.
Collapse
Affiliation(s)
- Jie Hu
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ni Gong
- Department of Nursing, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Dan Li
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Youyuan Deng
- Department of General Surgery, The Central Hospital of Xiangtan City, Xiangtan, Hunan, China
| | - Jiawei Chen
- Department of Rehabilitation, The Central Hospital of Xiangtan City, Xiangtan, Hunan, China
| | - Dingan Luo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Zhou
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China.
- Department of Radiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.
| | - Ke Xu
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China.
- Department of Oncology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China.
- Key Clinical Specialty of Sichuan Province, Chengdu, Sichuan, China.
| |
Collapse
|
|
9
|
Gou XX, Shi HY, Li C, Chen ZL, Ouyang W, Sun LY, Diao YK, Wang MD, Yao LQ, Gu LH, Pawlik TM, Lau WY, Shen F, Xue J, Yang T. Association of Adjuvant Radiation Therapy With Long-Term Overall and Recurrence-Free Survival After Hepatectomy for Hepatocellular Carcinoma: A Multicenter Propensity-Matched Study. Int J Radiat Oncol Biol Phys 2022; 114:238-249. [PMID: 35643251 DOI: 10.1016/j.ijrobp.2022.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE R0 resection with a wide surgical margin is the gold standard for hepatocellular carcinoma (HCC), yet R0 resection with narrow margins and even R1 resection is not uncommon in real-world clinical practice. We sought to use a propensity-matched analysis to characterize the efficacy of adjuvant radiation therapy on long-term oncological survival after hepatectomy for HCC with narrow or positive margins. METHODS AND MATERIALS Using a multi-institutional database, patients with HCC who underwent hepatectomy with negative margins of 0.1 to 1.0 cm or pathologically positive margins were analyzed. Using propensity score matching (PSM) and multivariate Cox-regression analysis, the effect of adjuvant radiation therapy on long-term overall survival (OS) and recurrence-free survival (RFS) was evaluated. RESULTS Among 683 patients who met inclusion criteria, 82 patients received adjuvant radiation therapy within 10 weeks after surgery. Radiation therapy-related major toxic effects were minimal among patients receiving adjuvant radiation therapy. PSM analysis created 78 matched pairs of patients. In the PSM cohort, median OS and RFS among patients treated with adjuvant radiation therapy were more favorable than individuals who were not treated (72.5 and 37.3 months versus 52.5 and 24.0 months, both P < .05). After adjustment for other confounding factors on multivariate analyses, adjuvant radiation therapy remained independently associated with favorable OS and RFS after hepatectomy with close/positive surgical margins for HCC (hazard ratios, 0.821 and 0.827, respectively). CONCLUSIONS Despite the lack of consensus on the role of adjuvant radiation therapy after HCC resection, this PSM analysis suggested improved OS and RFS with adjuvant radiation therapy after hepatectomy with close/positive surgical margins for HCC. Future randomized controlled trials are needed to further define the survival benefit of adjuvant radiation therapy for patients with HCC.
Collapse
Affiliation(s)
- Xiao-Xue Gou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
| | - Hong-Yun Shi
- Department of Radiotherapy, Affiliated Hospital of Hebei University, Baoding, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Zheng-Liang Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Harbin Medical University, Heilongjiang, China
| | - Wei Ouyang
- Department of Medical Oncology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Li-Yang Sun
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, Ohio
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jun Xue
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
10
|
Risk predictive model based on three immune-related gene pairs to assess prognosis and therapeutic sensitivity for hepatocellular carcinoma. World J Surg Oncol 2022; 20:252. [PMID: 35932027 PMCID: PMC9354375 DOI: 10.1186/s12957-022-02681-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 06/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) as a common tumor has a poor prognosis. Recently, a combination of atezolizumab and bevacizumab has been recommended as the preferred regimen for advanced HCC. However, the overall response rate of this therapy is low. There is an urgent need to identify sensitive individuals for this precise therapy among HCC patients. METHODS The Wilcox test was used to screen the differentially expressed immune-related genes by combining the TCGA cohort and the Immunology Database. Univariate and multivariate Cox regression analysis were used to screen the immune gene pairs concerning prognosis. A predictive model was constructed using LASSO Cox regression analysis, and correlation analysis was conducted between the signature and clinical characteristics. ICGC cohort and GSE14520 were applied for external validations of the predictive risk model. The relationship between immune cell infiltration, TMB, MSI, therapeutic sensitivity of immune checkpoint inhibitors, targeted drugs, and the risk model were assessed by bioinformatics analysis in HCC patients. RESULTS A risk predictive model consisting of 3 immune-related gene pairs was constructed and the risk score was proved as an independent prognostic factor for HCC patients combining the TCGA cohort. This predictive model exhibited a positive correlation with tumor size (p < 0.01) and tumor stage (TNM) (p < 0.001) in the chi-square test. The predictive power was verified by external validations (ICGC and GSE14520). The risk score clearly correlated with immune cell infiltration, MSI, immune checkpoints, and markers of angiogenesis. CONCLUSIONS Our research established a risk predictive model based on 3 immune-related gene pairs and explored its relationship with immune characteristics, which might help to assess the prognosis and treatment sensitivity to immune and targeted therapy of HCC patients.
Collapse
|
|
11
|
Qiu Y, Yang Y, Wang T, Shen S, Wang W. Efficacy of Postoperative Adjuvant Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma Patients With Microscopic Portal Vein Invasion. Front Oncol 2022; 12:831614. [PMID: 35795039 PMCID: PMC9252591 DOI: 10.3389/fonc.2022.831614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/24/2022] [Indexed: 12/04/2022] Open
Abstract
Background Microscopic portal vein invasion (MPVI) strongly predicts poor prognosis in patients with hepatocellular carcinoma (HCC). This study aims to investigate the impact of MPVI on the efficacy of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE). Methods From April 2014 to July 2019, a total of 512 HCC patients who underwent curative liver resection (LR) with microscopic vascular invasion (MVI) confirmed by histopathological examination were enrolled and divided into LR alone and PA-TACE groups. They were subsequently stratified into subgroups according to the presence of MPVI. Recurrence-free survival (RFS) and overall survival (OS) were compared using Kaplan–Meier curves and the log-rank test. The efficacy of PA-TACE was tested using univariate and multivariate Cox regression analyses. Sensitivity analysis was conducted after propensity score matching (PSM). Results Among all patients, 165 (32.3%) patients underwent PA-TACE, and 196 (38.2%) patients presented MPVI. In the entire cohort, PA-TACE and the presence of MPVI were identified as independent predictors for RFS and OS (all p<0.05). In the subgroup analysis, patients without MPVI who received PA-TACE had significantly better outcomes than those who underwent LR alone before and after PSM (all p<0.05). For patients with MPVI, PA-TACE displayed no significant benefit in terms of improving either RFS or OS, which was consistent with the results from the PSM cohort. Conclusion Among the HCC patients without MPVI who underwent curative liver resection, those who received PA-TACE had better RFS and OS outcomes than those who underwent LR alone. For patients with MPVI, PA-TACE had no significant effect on either RFS or OS outcomes.
Collapse
|
|
12
|
Wang KX, Du GH, Qin XM, Gao L. Compound Kushen Injection intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153781. [PMID: 34649212 DOI: 10.1016/j.phymed.2021.153781] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/14/2021] [Accepted: 09/25/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most extensive and most deadly cancers worldwide. The invasion and metastasis characteristics of HCC dramatically affect the prognosis and survival of HCC patients. Compound Kushen Injection (CKI) is a GMP produced, proverbially applied traditional Chinese medicine formula in China to treat cancer-associated pains, and used as an adjunctive therapy for HCC. Until so far, whether CKI could suppress the metastasis of HCC through regulation of epithelial-mesenchymal transition or metabolic reprogramming is still ambiguous. PURPOSE In this study, the anti-metastasis effects of CKI were clarified and its pharmacological mechanisms were systematically explored. METHODS Cell invasion and cell adhesion assay were performed in SMMC-7721 cells to assess the anti-metastasis role of CKI, and the histopathological evaluation and biochemical detection were utilized in DEN-induced HCC rats to verify the anti-HCC effect of CKI. Serum and liver samples were analyzed with 1H NMR metabolomics approach to screen the differential metabolites and further target quantification the content of key metabolites. Finally, western blotting and immunofluorescence assay were applied to verify the crucial signaling pathway involved in metabolites. RESULTS CKI markedly repressed the invasion and adhesion in SMMC-7721 cells and significantly improved the liver function of DEN-induced HCC rats. CKI significantly regulated the expression of epithelial-mesenchymal transition (EMT) markers (Vimentin and E-cadherin). Metabolomics results showed that CKI regulated the metabolic reprogramming of HCC by inhibiting the key metabolites (citrate and lactate) and enzymes (HK and PK) in glycolysis process. Importantly, we found that c-Myc mediates the inhibitory effect of CKI on glycolysis. We further demonstrated that CKI inhibits c-Myc expression through modulating Wnt/β-catenin pathway in SMMC-7721 cells and DEN-induced HCC rats. Furthermore, through activating Wnt/β-catenin pathway with LiCl, the inhibitory effects of CKI on HCC were diminished. CONCLUSION Together, this study reveals that CKI intervenes metabolic reprogramming and epithelial-mesenchymal transition of HCC via regulating β-catenin/c-Myc signaling pathway. Our research provides a new understanding of the mechanism of CKI against invasion and metastasis of HCC from the perspective of metabolic reprogramming.
Collapse
Affiliation(s)
- Ke-Xin Wang
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China
| | - Guan-Hua Du
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China.
| | - Li Gao
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan, China.
| |
Collapse
|
|
13
|
Glasgow Prognostic Score and modified Glasgow Prognostic Score and survival in patients with hepatocellular carcinoma: a meta-analysis. BMJ Open 2021. [PMCID: PMC8718431 DOI: 10.1136/bmjopen-2021-053061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective To evaluate the association between inflammation-related markers, modified Glasgow Prognostic Score (mGPS) and Glasgow Prognostic Score (GPS), and survival outcome and recurrence risk in patients with hepatocellular carcinoma (HCC) after treatment. Design Systematic reviews and meta-analysis of cohort studies. Date sources Embase, Scopus, Web of Science and PubMed were searched through 10 March 2021. Eligibility criteria We included cohort studies that assessed the effect of pretreatment mGPS/GPS levels on survival outcomes in patients with HCC. Data extraction and synthesis Two researchers independently selected the data and reached a consensus. In case of disagreement, a third researcher was required to assist. The HRs and 95% CIs were used as the effect size indexes. Newcastle-Ottawa Scale was used to assess risk of bias and quality assessment of the included studies. Results The meta-analysis included 23 studies, most of which were retrospective. Participants were grouped according to the score of mGPS/GPS. When analysed into two groups (1/2 vs 0), the results showed that patients with a mGPS/GPS of 1 or 2 had poorer overall survival (OS) than those with a score of 0 (both p<0.001). When analysed into three groups (1 vs 0 and 2 vs 0), the results revealed that an mGPS/GPS of 2 is related to poorer OS in patients with HCC (HR=2.46, 95% CI 2.06 to 2.95, and HR=3.45, 95% CI 1.68 to 7.10, respectively). However, a GPS of 1 (p=0.005) but not an mGPS of 1 (p=0.177) had a significant association with OS. No association was found between mGPS/GPS and disease-free survival or recurrence-free survival. Conclusion GPS was more closely associated the survival in patients with HCC than mGPS. A higher GPS has an association with poorer survival. It can be combined with tumour staging to assess the OS of HCC more accurately. PROSPERO registration number CRD42021242049.
Collapse
|
|
14
|
Gui L, Zhang S, Xu Y, Zhang H, Zhu Y, Kong L. UBE2S promotes cell chemoresistance through PTEN-AKT signaling in hepatocellular carcinoma. Cell Death Dis 2021; 7:357. [PMID: 34785642 PMCID: PMC8595659 DOI: 10.1038/s41420-021-00750-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/20/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022]
Abstract
Ubiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.
Collapse
Affiliation(s)
- Liang Gui
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Sicai Zhang
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Yongzi Xu
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Hongwei Zhang
- grid.452509.f0000 0004 1764 4566Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009 Nanjing, Jiangsu China
| | - Ying Zhu
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 210009, Nanjing, Jiangsu, China.
| | - Lianbao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, 210029, Nanjing, Jiangsu Province, China.
| |
Collapse
|
|
15
|
Xia X, Zhang H, Xia P, Zhu Y, Liu J, Xu K, Yuan Y. Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma. Front Oncol 2021; 11:733595. [PMID: 34527595 PMCID: PMC8437343 DOI: 10.3389/fonc.2021.733595] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/12/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND High glycolysis efficiency in tumor cells can promote tumor growth. lncRNAs play an important role in the proliferation, metabolism and migration of cancer cells, but their regulation of tumor glycolysis is currently not well researched. METHODS We analyzed the co-expression of glycolysis-related genes and lncRNAs in The Cancer Genome Atlas (TCGA) database to screen glycolysis-related lncRNAs. Further prognostic analysis and differential expression analysis were performed. We further analyzed the relationship between lncRNAs and tumor immune infiltration. Since WAC antisense RNA 1 (WAC-AS1) had the greatest effect on the prognosis among all screened lncRNAs and had a larger coefficient in the prognostic model, we chose WAC-AS1 for further verification experiments and investigated the function and mechanism of action of WAC-AS1 in hepatocellular carcinoma. RESULTS We screened 502 lncRNAs that have co-expression relationships with glycolytic genes based on co-expression analysis. Among them, 112 lncRNAs were abnormally expressed in liver cancer, and 40 lncRNAs were related to the prognosis of patients. Eight lncRNAs (WAC-AS1, SNHG3, SNHG12, MSC-AS1, MIR210HG, PTOV1-AS1, AC145207.5 and AL031985.3) were used to established a prognostic model. Independent prognostic analysis (P<0.001), survival analysis (P<0.001), receiver operating characteristic (ROC) curve analysis (AUC=0.779) and clinical correlation analysis (P<0.001) all indicated that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor (P<0.001). The risk score and lncRNAs in the model were found to be related to a variety of immune cell infiltration and immune functions. WAC-AS1 was found to affect glycolysis and promote tumor proliferation (P<0.01). WAC-AS1 affected the expression of several glycolysis-related genes (cAMP regulated phosphoprotein 19 (ARPP19), CHST12, MED24 and KIF2A) (P<0.01). Under hypoxic conditions, WAC-AS1 regulated ARPP19 by sponging miR-320d to promote glucose uptake and lactate production (P<0.01). CONCLUSION We constructed a model based on glycolysis-related lncRNAs to evaluate the prognostic risk of patients. The risk score and lncRNAs in the model were related to immune cell infiltration. WAC-AS1 can regulate ARPP19 to promote glycolysis and proliferation by sponging miR-320d.
Collapse
Affiliation(s)
- Xigang Xia
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Hao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Peng Xia
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Yimin Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Jie Liu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Kequan Xu
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| | - Yufeng Yuan
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, China
| |
Collapse
|
|
16
|
Zhang EL, Cheng Q, Huang ZY, Dong W. Revisiting Surgical Strategies for Hepatocellular Carcinoma With Microvascular Invasion. Front Oncol 2021; 11:691354. [PMID: 34123861 PMCID: PMC8190326 DOI: 10.3389/fonc.2021.691354] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Although liver resection (LR) and liver transplantation (LT) are widely considered as potentially curative therapies for selected patients with hepatocellular carcinoma (HCC); however, there is still high risk of tumor recurrence in majority of HCC patients. Previous studies demonstrated that the presence of microvascular invasion (MVI), which was defined as the presence of tumor emboli within the vessels adjacent to HCC, was one of the key factors of early HCC recurrence and poor surgical outcomes after LR or LT. In this review, we evaluated the impact of current MVI status on surgical outcomes after curative therapies and aimed to explore the surgical strategies for HCC based on different MVI status with evidence from pathological examination. Surgical outcomes of HCC patients with MVI have been described as a varied range after curative therapies due to a broad spectrum of current definitions for MVI. Therefore, an international consensus on the validated definition of MVI in HCC is urgently needed to provide a more consistent evaluation and reliable prediction of surgical outcomes for HCC patients after curative treatments. We concluded that MVI should be further sub-classified into MI (microvessel invasion) and MPVI (microscopic portal vein invasion); for HCC patients with MPVI, local R0 resection with a narrow or wide surgical margin will get the same surgical results. However, for HCC patients with MI, local surgical resection with a wide and negative surgical margin will get better surgical outcomes. Nowadays, MVI status can only be reliably confirmed by histopathologic evaluation of surgical specimens, limiting its clinical application. Taken together, preoperative assessment of MVI is of utmost significance for selecting a reasonable surgical modality and greatly improving the surgical outcomes of HCC patients, especially in those with liver cirrhosis.
Collapse
Affiliation(s)
- Er-Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Qi Cheng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| |
Collapse
|
|
17
|
Tani J, Senoh T, Moriya A, Ogawa C, Deguchi A, Sakamoto T, Takuma K, Nakahara M, Oura K, Tadokoro T, Mimura S, Fujita K, Yoneyama H, Kobara H, Morishita A, Himoto T, Tsutsui A, Nagano T, Takaguchi K, Masaki T. Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study. Cancers (Basel) 2021; 13:cancers13092257. [PMID: 34066708 PMCID: PMC8125844 DOI: 10.3390/cancers13092257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/09/2022] Open
Abstract
There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924-8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016-1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.
Collapse
Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
- Correspondence: ; Tel.: +81-87-891-2156
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kagawa 769-1695, Japan;
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Kagawa 760-0017, Japan;
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Kagawa 763-8502, Japan;
| | - Teppei Sakamoto
- Department of Internal Medicine, Yashima General Hospital, Kagawa 761-0816, Japan;
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa 761-0123, Japan;
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| |
Collapse
|
|
18
|
Intrahepatic recurrence of hepatocellular carcinoma after resection: an update. Clin J Gastroenterol 2021; 14:699-713. [PMID: 33774785 DOI: 10.1007/s12328-021-01394-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma recurrence occurs in 40-70% of patients after hepatic resection. Despite the high frequency of hepatocellular cancer relapse, there is no established guidance for the management of such cases. The evaluation of prognostic factors that indicate a high risk of recurrence after surgery such as the tumor number and size and the presence of microvascular invasion may guide the therapeutic strategy and point out which patients should be strictly monitored. Additionally, the administration of adjuvant treatment or ab initio liver transplantation in selected patients with high-risk characteristics could have a significant impact on the prevention of relapse and overall survival. Once the recurrence has occurred in the liver remnant, the available therapeutic options include re-resection, salvage liver transplantation and locoregional treatments, although the therapeutic choice is often challenging and should be based on the characteristics of the recurrent tumor, the patient profile and most importantly the timing of relapse. Aggressive combination treatments are often required in challenging cases of early relapse. The results of the above treatment strategies are reviewed and compared to determine the optimal management of patients with recurrent hepatocellular cancer following liver resection.
Collapse
|
|
19
|
Increased Visceral Adipose Tissue and Hyperinsulinemia Raise the Risk for Recurrence of Non-B Non-C Hepatocellular Carcinoma after Curative Treatment. Cancers (Basel) 2021; 13:cancers13071542. [PMID: 33810624 PMCID: PMC8036481 DOI: 10.3390/cancers13071542] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary With the increasing prevalence of obesity and diabetes in most countries, the increase in hepatocellular carcinoma (HCC) associated with these factors has recently become a serious healthcare problem. HCC can often emerge in the non-cirrhotic liver among obese patients, and it might suggest that the conventional surveillance strategies for HCC, which is mainly targeted at cirrhotic patients with hepatitis B or C virus, might be insufficient in the overnutrition era. We tried to extract factors that affect recurrence-free survival in patients with non-viral HCC, among obesity and diabetes factors, together with the established recurrence risk factors, using a decision-tree analysis. Abstract We investigated the factors affecting recurrence-free survival in patients with non-B non-C hepatocellular carcinoma (HCC) who received curative treatment. Decision-tree analysis was performed in 72 curative cases of non-B non-C HCC to extract the risk factors for recurrence. The reliability of the extracted risk factors was evaluated using the Kaplan–Meier method and the Cox proportional hazards model. The decision-tree analysis extracted three factors—visceral adipose tissue (VAT) index (VATI; <71 and ≥71 cm2/m2), which was the cross-sectional areas of VAT on the computed tomographic image at the umbilical level, normalized by the square of the height, fasting immunoreactive insulin (FIRI; <5.5 and ≥5.5 µU/mL), and alpha-fetoprotein (AFP; <11 and ≥11 ng/mL). The Cox proportional hazards model showed that VATI (hazard ratio (HR): 2.556, 95% confidence interval (CI): 1.191–5.486, p = 0.016), FIRI (HR: 3.149, 95% CI: 1.156–8.575, p = 0.025), and AFP (HR: 3.362, 95% CI: 1.550–7.288, p = 0.002) were all independent risk factors for HCC recurrence. Non-B non-C HCC patients with a higher VATI (≥71 cm2/m2) or higher FIRI (≥5.5 µU/mL) and AFP (≥11 ng/mL) if VATI was <71 cm2/m2 are prone to recurrence after curative treatment.
Collapse
|
|
20
|
Lin S, Lin Y, Fang Y, Mo Z, Hong X, Ji C, Jian Z. Clinicopathological and prognostic value of preoperative lymphocyte to monocyte ratio for hepatocellular carcinoma following curative resection: A meta-analysis including 4,092 patients. Medicine (Baltimore) 2021; 100:e24153. [PMID: 33546030 PMCID: PMC7837861 DOI: 10.1097/md.0000000000024153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 12/05/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Previous studies have reported that lymphocyte-to-monocyte ratio (LMR) had novel prognostic value in hepatocellular carcinoma (HCC). The purpose of this meta-analysis was to synthetically evaluate the prognostic role of preoperative LMR in HCC patients following curative resection. METHODS Eligible studies were acquired through searching Pubmed, Web of Science, Cochrane Library and EMbase update to September 2019. Merged hazard ratios (HRs) and 95% confidence intervals (CIs) were applied as effect sizes. RESULTS A total of ten studies containing 4,092 patients following liver resection were enrolled in this meta-analysis. The pooled results demonstrated that preoperative elevated LMR indicated superior survival outcome (HR: 0.58, 95% CI: 0.34-0.96, P = .035) and recurrence-free survival (RFS)/disease-free survival/time to recurrence (HR = 0.76, 95% CI: 0.58-0.98, P = .034). The significant prognostic role of preoperative LMR was detected in the subgroup of all publication year, country of origin, sample sizes <300, TNM stage of I-IV and LMR cut-off value ≤4. Furthermore, high LMR was significantly associated with male, high AFP, large tumor size, incomplete tumor capsule, advanced TNM stage and BCLC stage, and presence of PVTT. CONCLUSION Elevated preoperative LMR indicated superior survival outcome in HCC patients following curative resection, and might serve as a novel prognostic biomarker.
Collapse
Affiliation(s)
| | - Ye Lin
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China
| | - Yinghua Fang
- Department of pain, Binhaiwan Central Hospital of Dongguan, (also called The Fifth People's Hospital of Dongguan), The Dongguan Affiliated Hospital of Medical College of Jinan University, Dongguan
| | | | | | | | - Zhixiang Jian
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China
| |
Collapse
|
|
21
|
Zhang CC, Zhang CW, Xing H, Wang Y, Liang L, Diao YK, Chen TH, Lau WY, Bie P, Chen ZY, Yang T. Preoperative Inversed Albumin-to-Globulin Ratio Predicts Worse Oncologic Prognosis Following Curative Hepatectomy for Hepatocellular Carcinoma. Cancer Manag Res 2020; 12:9929-9939. [PMID: 33116850 PMCID: PMC7567562 DOI: 10.2147/cmar.s275307] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/16/2020] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND A normal albumin-to-globulin ratio (NAGR) in serum is greater than 1. Inversed albumin-to-globulin ratio (IAGR < 1) indicates poor synthetic liver function or malnutrition. The aim of this study is to evaluate whether preoperative IAGR was associated with worse oncologic survival after hepatectomy for hepatocellular carcinoma (HCC). PATIENTS AND METHODS Patients who underwent curative hepatectomy for HCC between 2009 and 2016 in four centers were divided into the IAGR and NAGR groups based on their preoperative levels, and their clinical characteristics and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors of overall survival (OS) and recurrence-free survival (RFS). RESULTS Of 693 enrolled patients, 136 (19.6%) were in the IAGR group. Their 5-year OS and RFS rates were 31.6% and 21.3%, respectively, which were significantly worse than the NAGR group (43.4% and 28.7%, both P < 0.001). The area under the receiver operating characteristic curves in predicting 5-year OS and RFS using the albumin-to-globulin ratio were 0.68 and 0.67, respectively, which were significantly higher than albumin (0.60 and 0.59), globulin (0.56 and 0.57), Child-Pugh grading (0.61 and 0.60), Model for End-Stage Liver Disease Score (0.59 and 0.58), and Albumin-Bilirubin grading (0.64 and 0.63). Multivariable analyses identified that preoperative IAGR was independently associated with worse OS (HR: 1.444, 95% confidence interval (CI): 1.125-1.854, P = 0.004) and RFS (HR: 1.463, 95% CI: 1.159-1.848, P = 0.001). CONCLUSION Preoperative IAGR was useful in predicting worse OS and RFS in patients who underwent curative hepatectomy for HCC.
Collapse
Affiliation(s)
- Cheng-Cheng Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Cheng-Wu Zhang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Yu Wang
- Department of Hepatobiliary Surgery, Chongqing University Cancer Hospital, Chongqing, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Yong-Kang Diao
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People’s Hospital, Sichuan, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Ping Bie
- Department of Hepatobiliary, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhi-Yu Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| |
Collapse
|
|
22
|
Luo D, Li H, Yu H, Zhang M, Hu J, Jin C, Chua M, Han B. Predictive value of preoperative and postoperative peripheral lymphocyte difference in hepatitis B virus-related hepatocellular cancer patients: Based on the analysis of dynamic nomogram. J Surg Oncol 2020; 122:1553-1568. [PMID: 32862430 DOI: 10.1002/jso.26195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 08/15/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Inflammation plays an important role in the progression and prognosis of hepatocellular carcinoma (HCC). Our aim is to explore the prognostic value of preoperative and postoperative peripheral lymphocyte differences and to develop a dynamic prognosis nomogram in hepatitis B virus-related HCC patients. METHODS Important indicators related to overall survival (OS) are screened out by Cox proportional hazard models. The receiver operating characteristic curves, decision curve analysis curves, net reclassification improvement, and integrated discrimination improvement were used to evaluate the performance of the model. RESULTS Lymphocyte (L) difference was an independent risk factor. It was further verified that the performance of the nomogram was significantly improved after the L difference was incorporated into the nomogram. The nomogram generated had the area under curves of 0.779, 0.775, and 0.793 at 3, 5, and 7 years after surgery, respectively. Our nomogram models showed significantly better performance in predicting the HCC prognosis compared to other models. And online webserver and scoring system table was built based on the proposed nomogram for convenient clinical use. CONCLUSIONS It is newly found that L difference is an effective predictor of OS, and the nomogram based on this indicator can accurately predict the prognosis of HCC patients.
Collapse
Affiliation(s)
- Dingan Luo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Haoran Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Heng Yu
- Department of Radiation Oncology, Stanford Medical School, Stanford University, Stanford, California
| | - Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jianchong Hu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cheng Jin
- Department of Radiation Oncology, Stanford Medical School, Stanford University, Stanford, California
| | - Meisze Chua
- Department of Surgery, Asian Liver Center, Stanford University School of Medicine, Stanford, California
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|
|
23
|
Chen D, Wang Y, Lu R, Jiang X, Chen X, Meng N, Chen M, Xie S, Yan GR. E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing. Theranostics 2020; 10:8558-8572. [PMID: 32754263 PMCID: PMC7392027 DOI: 10.7150/thno.44873] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/24/2020] [Indexed: 12/18/2022] Open
Abstract
Rationale: Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and few molecularly targeted anticancer therapies have been developed to treat it. Thus, the identification of new therapeutic targets is urgent. Metabolic reprogramming is an important hallmark of cancer. However, how ubiquitin ligases are involved in the regulation of cancer metabolism remains poorly understood. Methods: RT-PCR, western blot and IHC were used to determine ZFP91 expression. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of ZFP91. Mouse xenograft models were used to study the in vivo effects of ZFP91. Co-IP together with mass spectrometry or western blot was utilized to investigate protein-protein interaction. Ubiquitination was analyzed using IP together with western blot. RNA splicing was assessed by using RT-PCR followed by restriction digestion. Lactate production and glucose uptake assays were used to analyze cancer metabolism. Results: We identified that an E3 ligase zinc finger protein 91 (ZFP91) suppressed HCC metabolic reprogramming, cell proliferation and metastasis in vitro and in vivo. Mechanistically, ZFP91 promoted the Lys48-linked ubiquitination of the oncoprotein hnRNP A1 at lysine 8 and proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM splicing, subsequently resulting in higher PKM1 isoform formation and lower PKM2 isoform formation and suppressing HCC glucose metabolism reprogramming, cell proliferation and metastasis. Moreover, HCC patients with lower levels of ZFP91 have poorer prognoses, and ZFP91 is an independent prognostic factor for patients with HCC. Conclusions: Our study identifies ZFP91 as a tumor suppressor of hepatocarcinogenesis and HCC metabolism reprogramming and proposes it as a novel prognostic biomarker and therapeutic target of HCC.
Collapse
Affiliation(s)
- De Chen
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Yanjie Wang
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Ruixun Lu
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Xiaofeng Jiang
- Department of Surgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China
| | - Xinhui Chen
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Nan Meng
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Min Chen
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Shan Xie
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Guang-Rong Yan
- Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, 511436, China
| |
Collapse
|
|
24
|
Zhao Y, Yu YQ, You S, Zhang CM, Wu L, Zhao W, Wang XM. Long Non-Coding RNA MALAT1 as a Detection and Diagnostic Molecular Marker in Various Human Cancers: A Pooled Analysis Based on 3255 Subjects. Onco Targets Ther 2020; 13:5807-5817. [PMID: 32606791 PMCID: PMC7311208 DOI: 10.2147/ott.s250796] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/20/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose Accumulating studies have explored the potential diagnostic value of lncRNA MALAT1 in various cancers. However, there are still inconsistent results in diagnostic accuracy and reliability in individual studies. The aim of this pooled study was to summarize the overall diagnostic capacity of lncRNA MALAT1 in cancer detection and diagnosis. Methods Eligible studies satisfying the inclusion criteria were screened and selected from the online database. All statistical analyses were performed using Stata 14.0. Results A total of 17 eligible studies were included in this pooled analysis, with 1777 cases and 1478 controls. The overall results were shown as follows: sensitivity, 0.74 (95% CI=0.65-0.81), specificity, 0.79 (95% CI=0.73-0.84), positive likelihood ratio (PLR), 3.48 (95% CI=2.79-4.32), negative likelihood, 0.33 (95% CI=0.25-0.44), diagnostic score, 2.34 (95% CI=1.99-2.69), diagnostic odds ratio, 10.41 (95% CI=7.33-14.78) and area under the curve, 0.83 (95% CI=0.80-0.86). Deeks' funnel plot asymmetry test (p = 0.66) suggested no potential publication bias. Conclusion All these results indicate that lncRNA MALAT1 achieves a relatively moderate accuracy in cancer detection and diagnosis, and could serve as a diagnostic biomarker for cancers.
Collapse
Affiliation(s)
- Yue Zhao
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People's Republic of China.,Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich 81377, Germany
| | - Ya-Qi Yu
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People's Republic of China
| | - Song You
- Mengchao Hepatobiliary Hospital of Fujian Medical University, The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Chang-Mao Zhang
- Faculty of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, People's Republic of China
| | - Liang Wu
- Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Wenxiu Zhao
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People's Republic of China
| | - Xiao-Min Wang
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People's Republic of China
| |
Collapse
|
|
25
|
Chen ZY, Wang T, Gan X, Chen SH, He YT, Wang YQ, Zhang KH. Cytoskeleton-associated membrane protein 4 is upregulated in tumor tissues and is associated with clinicopathological characteristics and prognosis in hepatocellular carcinoma. Oncol Lett 2020; 19:3889-3898. [PMID: 32382336 PMCID: PMC7202277 DOI: 10.3892/ol.2020.11499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 02/21/2020] [Indexed: 12/24/2022] Open
Abstract
The role of cytoskeleton-associated membrane protein 4 (CKAP4) in hepatocellular carcinoma (HCC) is controversial. The present study aimed to investigate the association between tumor CKAP4 mRNA expression and clinicopathological characteristics and prognosis in patients with HCC. Data relating to CKAP4 mRNA expression in HCC tumor and normal adjacent liver tissues, and clinicopathological characteristics, were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The CKAP4 mRNA levels in tumor tissues were compared with those in normal adjacent liver tissues, their association with clinicopathological parameters was analyzed, and diagnostic and prognostic values were evaluated in patients with HCC. In all 4 datasets (total samples, n=693), CKAP4 mRNA levels were significantly higher in tumor tissues compared with adjacent tissues (all P<0.001), with the area under the receiver operating characteristic curve ranging from 0.799-0.898 for HCC diagnosis. In patients with HCC with available clinical data (n=361), the low-level CKAP4 mRNA group exhibited a lower body mass index (P=0.005), higher α-fetoprotein level (P<0.001), more frequent adjacent liver tissue inflammation (P<0.001), poorer tumor histological grade (P<0.001), higher Ishak fibrosis score (P=0.035) and a more advanced tumor node metastasis (TNM) stage (P=0.014) compared with the high-level CKAP4 mRNA group. Patients stratified by all the above parameters, except for TNM stage, exhibited significantly different expression of tissue CKAP4 mRNA (P<0.05-0.001). Furthermore, higher CKAP4 mRNA levels were observed in patients who died within one year following diagnosis compared with those who survived >3 years (P=0.003). The high-level CKAP4 mRNA group also exhibited lower overall survival (OS) and disease-free survival (DFS) rates compared with the low-level group [hazard ratio (HR)=1.494; 95% confidence interval (CI), 1.044-2.138; P=0.028] for OS and (HR=1.616; 95% CI, 1.022-2.555; P=0.040) for DFS. The results of the present study suggest that CKAP4 mRNA is upregulated in HCC tumor tissues compared with normal adjacent tissues, and is associated with poor clinical prognosis, pathological features and survival in patients with HCC. Thus, CKAP4 is a potential biomarker for HCC diagnosis and prognosis.
Collapse
Affiliation(s)
- Zhi-Yong Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| | - Ting Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| | - Xia Gan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China.,Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Si-Hai Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| | - Yu-Ting He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| | - Yu-Qi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| | - Kun-He Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology and Hepatology, Nanchang, Jiangxi 330006, P.R. China
| |
Collapse
|
|
26
|
Xing H, Zhang WG, Cescon M, Liang L, Li C, Wang MD, Wu H, Lau WY, Zhou YH, Gu WM, Wang H, Chen TH, Zeng YY, Schwartz M, Pawlik TM, Serenari M, Shen F, Wu MC, Yang T. Defining and predicting early recurrence after liver resection of hepatocellular carcinoma: a multi-institutional study. HPB (Oxford) 2020; 22:677-689. [PMID: 31607637 DOI: 10.1016/j.hpb.2019.09.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/12/2019] [Accepted: 09/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND A clear definition of "early recurrence" after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence. METHODS Patients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort. RESULTS Among 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction). CONCLUSIONS An interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC.
Collapse
Affiliation(s)
- Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan-Guang Zhang
- Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Matteo Cescon
- Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy
| | - Lei Liang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong Special Administrative Region
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Wei-Min Gu
- The First Department of General Surgery, The Fourth Hospital of Harbin, Heilongjiang, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Myron Schwartz
- Liver Cancer Program, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Matteo Serenari
- Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Meng-Chao Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| |
Collapse
|
|
27
|
Lin X, Huang Y, Sun Y, Tan X, Ouyang J, Zhao B, Wang Y, Xing X, Liu J. 4E-BP1 Thr46 Phosphorylation Association with Poor Prognosis in Quantitative Phosphoproteomics of Portal Vein Tumor Thrombus Revealed that 4E-BP1Thr46 Phosphorylation is Associated with Poor Prognosis in HCC. Cancer Manag Res 2020; 12:103-115. [PMID: 32021427 PMCID: PMC6954833 DOI: 10.2147/cmar.s230849] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/30/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose Early formation of portal vein tumor thrombosis (PVTT) is a key characteristic of hepatocellular carcinoma (HCC) metastasis, but to date, the aetiology of PVTT in HCC metastasis is largely unknown. We aim to find highly sensitive and specific biomarkers for the prediction of HCC prognosis. Patients and methods We used isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative phosphoproteomics approach to investigate the molecular signatures of the HCC with PVTT in primary HCC tissues, surrounding non-cancerous tissues and PVTT tissues. The different proteome profiles in three groups were investigated and might reveal different underlying molecular mechanisms. Results In total, we identified 1745 phosphoproteins with 2724 phosphopeptides and 4594 phosphorylation sites in three groups. Among these phosphoproteins, 80 phosphoproteins were dysregulated in PVTT/Pan group, 51 phosphoproteins were dysregulated in HCC/Pan group, and 10 phosphoproteins were dysregulated in PVTT/HCC group. Furthermore, the phosphorylation of 4E-BP1 was elevated in HCC tissues and PVTT tissues in comparison with surrounding non-cancerous tissues, and the elevated fold change of phosphorylation level was higher than that in expression level of 4E-BP1. The further IHC analysis in acohort of 20 HCC tissues showed that the phosphorylation of 4E-BP1 on Thr46 might be closely related to HCC prognosis. Conclusion The high phosphorylation level of 4E-BP1Thr46 might serve as a biomarker for the diagnosis of early recurrence and metastasis of HCC.
Collapse
Affiliation(s)
- Xincong Lin
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Yao Huang
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Ying Sun
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Xionghong Tan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Jiahe Ouyang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Xiaohua Xing
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Jingfeng Liu
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China.,The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| |
Collapse
|
|
28
|
Hong W, Hu Y, Fan Z, Gao R, Yang R, Bi J, Hou J. In silico identification of EP400 and TIA1 as critical transcription factors involved in human hepatocellular carcinoma relapse. Oncol Lett 2019; 19:952-964. [PMID: 31897208 PMCID: PMC6924164 DOI: 10.3892/ol.2019.11171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 10/22/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated mortality worldwide. Transcription factors (TFs) are crucial proteins that regulate gene expression during cancer progression; however, the roles of TFs in HCC relapse remain unclear. To identify the TFs that drive HCC relapse, the present study constructed co-expression network and identified the Tan module the most relevant to HCC relapse. Numerous hub TFs (highly connected) were subsequently obtained from the Tan module according to the intra-module connectivity and the protein-protein interaction network connectivity. Next, E1A-binding protein p400 (EP400) and TIA1 cytotoxic granule associated RNA binding protein (TIA1) were identified as hub TFs differentially connected between the relapsed and non-relapsed subnetworks. In addition, zinc finger protein 143 (ZNF143) and Yin Yang 1 (YY1) were also identified by using the plugin iRegulon in Cytoscape as master upstream regulatory elements, which could potentially regulate expression of the genes and TFs of the Tan module, respectively. The Kaplan-Meier (KM) curves obtained from KMplot and Gene Expression Profiling Interactive Analysis tools confirmed that the high expression of EP400 and TIA1 were significantly associated with shorter relapse-free survival and disease-free survival of patients with HCC. Furthermore, the KM curves from the UALCAN database demonstrated that high EP400 expression significantly reduced the overall survival of patients with HCC. EP400 and TIA1 may therefore serve as potential prognostic and therapeutic biomarkers.
Collapse
Affiliation(s)
- Weiguo Hong
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Yan Hu
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Zhenping Fan
- Liver Disease Center for Cadre Medical Care, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Rong Gao
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Ruichuang Yang
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Jingfeng Bi
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| | - Jun Hou
- Clinical Research and Management Center, Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, P.R. China
| |
Collapse
|
|
29
|
Imai K, Takai K, Hanai T, Suetsugu A, Shiraki M, Shimizu M. Sustained virological response by direct-acting antivirals reduces the recurrence risk of hepatitis C-related hepatocellular carcinoma after curative treatment. Mol Clin Oncol 2019; 12:111-116. [PMID: 31929880 PMCID: PMC6951252 DOI: 10.3892/mco.2019.1956] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/09/2019] [Indexed: 02/06/2023] Open
Abstract
The present study aimed to assess the suppressive effect of direct-acting antivirals (DAAs) on hepatocellular carcinoma (HCC) recurrence following curative treatment, particularly compared with interferon (IFN)-based therapy. Among 117 curative cases of HCV-related initial HCC between 2006 and 2017 at Gifu University Hospital, 13 and 14 cases achieved a sustained virological response (SVR) by DAA- (DAA group) or IFN-based therapies (IFN group), and 64 cases were not treated with any antiviral therapy (non-treatment group). Recurrence-free survival (RFS) following curative treatment in each group was analyzed using the Kaplan-Meier method and log-rank test. A Cox proportional hazards model was used to analyze the factors that affected RFS. Age was significantly lower and serum alanine aminotransferase level was significantly higher in the IFN group than in both the DAA and non-treatment groups. There was a significant difference in RFS between the non-treatment group and antiviral therapy groups, including the DAA (P=0.014) and IFN groups (P=0.009); however, no significant difference was identified in RFS between the DAA and IFN groups (P=0.564). SVR achieved by DAA [P=0.011; hazard ratio (HR), 0.222; 95% CI, 0.069-0.758] or IFN therapy (P=0.007; HR, 0.327; 95% CI, 0.145-0.742) was an independent factor for the prevention of HCC recurrence. SVR by DAA therapy exhibited an anti-liver tumorigenesis effect equal to that of IFN-based therapy and reduced the risk of HCC recurrence.
Collapse
Affiliation(s)
- Kenji Imai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Koji Takai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Makoto Shiraki
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| |
Collapse
|
|
30
|
Hu P, Fu Z, Liu G, Tan H, Xiao J, Shi H, Cheng D. Gadolinium-Based Nanoparticles for Theranostic MRI-Guided Radiosensitization in Hepatocellular Carcinoma. Front Bioeng Biotechnol 2019; 7:368. [PMID: 31828068 PMCID: PMC6890599 DOI: 10.3389/fbioe.2019.00368] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/13/2019] [Indexed: 12/30/2022] Open
Abstract
Background: Radiation therapy (RT) of hepatocellular carcinoma (HCC) is limited by low tolerance of the liver to radiation, whereas radiosensitizers are effective in reducing the required radiation dose. Multimodality gadolinium-based nanoparticles (AGuIX) are small and have enhanced permeability and retention effects; thus, they are very suitable for radiation sensitizer HCC RT. Here, we evaluated the potential value of AGuIX for theranostic MRI-radiosensitization in HCC. Methods: The radiosensitization effects of AGuIX were evaluated via in vitro and in vivo experiments. Tumor growth, apoptosis imaging, and immunohistochemistry were performed to verify the antitumor effects of RT with AGuIX. Results:In vitro evaluation of the efficacy of radiosensitivity of the AGuIX demonstrated that the presence of AGuIX significantly decreased HepG2 cell survival when combined with an X-ray beam. In vivo MRI imaging showed the ratio of tumor/liver concentration of the AGuIX was the highest 1 h after intravenous injection. For antitumor effects, we found that the tumor size decreased by RT-only and RT with AGuIX. The antitumor effects were more effective with high-dose AGuIX-mediated RT. Apoptosis imaging and immunohistochemistry both demonstrated that the degree of the cell apoptosis was highest with a high dose of AGuIX-mediated RT. Conclusions: This study provides compelling data that AGuIX can facilitate theranostic MRI-radiosensitization in HCC.
Collapse
Affiliation(s)
- Pengcheng Hu
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhequan Fu
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guobing Liu
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui Tan
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Xiao
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongcheng Shi
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Medical Imaging, Shanghai, China
| | - Dengfeng Cheng
- Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Medical Imaging, Shanghai, China
| |
Collapse
|
|
31
|
Yamamoto M, Kobayashi T, Kuroda S, Hamaoka M, Okimoto S, Honmyo N, Yamaguchi M, Ohdan H. Verification of inflammation-based prognostic marker as a prognostic indicator in hepatocellular carcinoma. Ann Gastroenterol Surg 2019; 3:667-675. [PMID: 31788655 PMCID: PMC6875930 DOI: 10.1002/ags3.12286] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/29/2019] [Accepted: 08/14/2019] [Indexed: 12/14/2022] Open
Abstract
AIM Although inflammation-based markers in cancer have been used for prognostic prediction, the most useful marker for hepatocellular carcinoma (HCC) has not been established. We investigated the usefulness of various inflammation-based markers in HCC patients after hepatectomy. METHODS A total of 478 patients who underwent initial hepatectomy for HCC from 2009 to 2015 and were diagnosed with pathological HCC were included in this retrospective study. Inflammation-based markers consisted of the C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS), neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, platelet to lymphocyte ratio and prognostic index. Univariate and multivariate analyses for overall survival (OS) and disease-free survival (DFS) using the Cox proportional hazard model were carried out. Kaplan-Meier analysis and log-rank test were used for comparison of OS and DFS. To reduce influences of selection bias and confounders for stratifying CAR, clinicopathological characteristics of patients were balanced by propensity score matching. RESULTS Multivariate analysis identified only high CAR (>0.027) as an indicator of poor OS, and high CAR and high GPS (1-2) as indicators of poor DFS among inflammation-based markers. After propensity score matching, 124 patients each with low CAR and high CAR were matched. High CAR was correlated with both poor OS and DFS. CONCLUSION C-reactive protein to albumin ratio was the most valuable prognostic indicator after hepatectomy for HCC among inflammation-based markers.
Collapse
Affiliation(s)
- Masateru Yamamoto
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Michinori Hamaoka
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Sho Okimoto
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Naruhiko Honmyo
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Megumi Yamaguchi
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant SurgeryGraduate School of Biomedical and Health ScienceHiroshima UniversityHiroshimaJapan
| |
Collapse
|
|
32
|
Imai K, Takai K, Miwa T, Taguchi D, Hanai T, Suetsugu A, Shiraki M, Shimizu M. Rapid Depletions of Subcutaneous Fat Mass and Skeletal Muscle Mass Predict Worse Survival in Patients with Hepatocellular Carcinoma Treated with Sorafenib. Cancers (Basel) 2019; 11:E1206. [PMID: 31430945 PMCID: PMC6721466 DOI: 10.3390/cancers11081206] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/14/2019] [Accepted: 08/16/2019] [Indexed: 02/07/2023] Open
Abstract
The aim of this study was to investigate whether rapid depletions of fat mass and skeletal muscle mass predict mortality in hepatocellular carcinoma (HCC) patients treated with sorafenib. This retrospective study evaluated 61 HCC patients. The cross-sectional areas of visceral and subcutaneous fat mass and skeletal muscle mass were measured by computed tomography, from which the visceral fat mass index (VFMI), subcutaneous fat mass index (SFMI), and skeletal muscle index (L3SMI) were obtained. The relative changes in these indices per 120 days (ΔVFMI, ΔSFMI, and ΔL3SMI) before and after sorafenib treatment were calculated in each patient. Patients within the 20th percentile cutoffs for these indices were classified into the rapid depletion (RD) group. Kaplan-Meier analysis revealed that with respect to ΔL3SMI (p = 0.0101) and ΔSFMI (p = 0.0027), the RD group had a significantly poorer survival. Multivariate analysis using the Cox proportional-hazards model also demonstrated that ΔL3SMI (≤-5.73 vs. >-5.73; hazard ratio [HR]: 4.010, 95% confidence interval [CI]: 1.799-8.938, p = < 0.001) and ΔSFMI (≤-5.33 vs. >-5.33; HR: 4.109, 95% CI: 1.967-8.584, p = < 0.001) were independent predictors. Rapid depletions of subcutaneous fat mass and skeletal muscle mass after the introduction of sorafenib indicate a poor prognosis.
Collapse
Affiliation(s)
- Kenji Imai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
| | - Koji Takai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Daisuke Taguchi
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Makoto Shiraki
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| |
Collapse
|
|
33
|
Han J, Li ZL, Xing H, Wu H, Zhu P, Lau WY, Zhou YH, Gu WM, Wang H, Chen TH, Zeng YY, Wu MC, Shen F, Yang T. The impact of resection margin and microvascular invasion on long-term prognosis after curative resection of hepatocellular carcinoma: a multi-institutional study. HPB (Oxford) 2019; 21:962-971. [PMID: 30718183 DOI: 10.1016/j.hpb.2018.11.005] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for hepatocellular carcinoma (HCC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes. METHODS Using multi-institutional data, the different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive or negative) on overall survival (OS) and recurrence-free survival (RFS) after curative liver resection of solitary HCC without macrovascular invasion was analyzed. RESULTS In 801 patients, 306 (38%) had a narrow RM and 352 (44%) had positive MVI. The median OS and RFS were 109.8 and 74.8 months in patients with wide RM & negative MVI, 93.5 and 53.1 months with wide RM & positive MVI, 79.2 and 41.6 months with narrow RM & negative MVI, and 69.2 and 37.5 months with narrow RM & positive MVI (both P < 0.01). On multivariable analyses, narrow RM & positive MVI had the highest hazard ratio with reduced OS and RFS (HR 2.96, 95% CI 2.11-4.17, and HR 3.15, 95% CI, 2.09-4.67, respectively). CONCLUSIONS Concomitant having narrow RM and positive MVI increases the risks of postoperative death and recurrence by about 2-fold in patients with solitary HCC.
Collapse
Affiliation(s)
- Jun Han
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhen-Li Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Peng Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR
| | - Ya-Hao Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - Wei-Min Gu
- The First Department of General Surgery, The Fourth Hospital of Harbin, Heilongjiang, China
| | - Hong Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - Ting-Hao Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Meng-Chao Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| |
Collapse
|
|
34
|
Yang T, Liu K, Liu CF, Zhong Q, Zhang J, Yu JJ, Liang L, Li C, Wang MD, Li ZL, Wu H, Xing H, Han J, Lau WY, Zeng YY, Zhou YH, Gu WM, Wang H, Chen TH, Zhang YM, Zhang WG, Pawlik TM, Wu MC, Shen F. Impact of postoperative infective complications on long-term survival after liver resection for hepatocellular carcinoma. Br J Surg 2019; 106:1228-1236. [PMID: 31276196 DOI: 10.1002/bjs.11231] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/05/2019] [Accepted: 04/11/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important role. The aim of this study was to evaluate whether postoperative infective complications influence long-term survival after liver resection for hepatocellular carcinoma (HCC). METHODS Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence-free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection. RESULTS Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021). CONCLUSION Postoperative infective complications decreased long-term OS and RFS in patients treated with liver resection for HCC.
Collapse
Affiliation(s)
- T Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - K Liu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - C-F Liu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Q Zhong
- Department of Anaesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - J Zhang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - J-J Yu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - L Liang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - C Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - M-D Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Z-L Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - H Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - H Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - J Han
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - W Y Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- Faculty of Medicine, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Y-Y Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fujian, China
| | - Y-H Zhou
- Department of Hepatobiliary Surgery, Pu'er People's Hospital, Yunnan, China
| | - W-M Gu
- First Department of General Surgery, Fourth Hospital of Harbin, Heilongjiang, China
| | - H Wang
- Department of General Surgery, Liuyang People's Hospital, Hunan, China
| | - T-H Chen
- Department of General Surgery, Ziyang First People's Hospital, Sichuan, China
| | - Y-M Zhang
- Second Department of Hepatobiliary Surgery, Meizhou People's Hospital, Guangdong, China
| | - W-G Zhang
- Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - T M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - M-C Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - F Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
35
|
Zhao Y, Yu Y, Zhao W, You S, Feng M, Xie C, Chi X, Zhang Y, Wang X. As a downstream target of the AKT pathway, NPTX1 inhibits proliferation and promotes apoptosis in hepatocellular carcinoma. Biosci Rep 2019; 39:BSR20181662. [PMID: 31113871 PMCID: PMC6549097 DOI: 10.1042/bsr20181662] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 04/26/2019] [Accepted: 05/20/2019] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is correlated with a poor prognosis and high mortality worldwide. Neuronal pentraxin 1 (NPTX1) has been reported to play an oncogenic role in several types of tumors. However, its expression and function in HCC is not yet fully understood. In the present study, we aimed to investigate the clinicopathological significance of NPTX1 in HCC and the underlying mechanisms. We observed that the expression of NPTX1 was decreased significantly in HCC and was associated with tumor size and metastasis in patients. Gain-of-function approaches revealed that NPTX1 suppressed the growth ability of HCC cells and contributed to mitochondria- related apoptosis. Furthermore, mechanistic investigations showed that the AKT (AKT serine/threonine kinase) pathway can regulate the effects of NPTX1 in HCC cells. After blocking the AKT pathway, the action of NPTX1 was greatly increased. In summary, we demonstrated that NPTX1 inhibited growth and promoted apoptosis in HCC via an AKT-mediated signaling mechanism. These findings indicate that NPTX1 is a potential clinical therapeutic target.
Collapse
Affiliation(s)
- Yue Zhao
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Yaqi Yu
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Wenxiu Zhao
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Song You
- Faculty of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Min Feng
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Chengrong Xie
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Xiaoqin Chi
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| | - Yi Zhang
- Faculty of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, P.R. China
| | - Xiaomin Wang
- Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian, P.R. China
| |
Collapse
|
|
36
|
Zhang M, Hu J, Li H, Zhang S, Hu W, Wu L, Han B. High TNF-α and/or p38MAPK expression predicts a favourable prognosis in patients with T 1N 0M 0 hepatocellular carcinoma: An immunohistochemical study. Oncol Lett 2019; 17:4948-4956. [PMID: 31186704 PMCID: PMC6507481 DOI: 10.3892/ol.2019.10193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/29/2019] [Indexed: 02/06/2023] Open
Abstract
Tumour necrosis factor α (TNF-α) and p38 mitogen-activated protein kinase (p38MAPK) serve an important role in regulating tumour cell apoptosis. However, a limited number of studies have investigated the predictive value of both TNF-α and p38MAPK in hepatocellular carcinoma (HCC). An integrated bioinformatics analysis was initially performed using two datasets available from the Oncomine™ database to determine the association between TNF-α and/or p38MAPK expression and prognosis of patients with HCC. Subsequently, TNF-α and p38MAPK expression in tissue samples from 83 patients with HCC classified as T1N0M0, using the Tumour-Node-Metastasis (TNM) staging system, was investigated using immunohistochemistry. The associations between clinicopathological characteristics and different TNF-α and p38MAPK expression levels in HCC were investigated using the χ2 test. Kaplan-Meier and Cox univariate/multivariate survival analyses were performed to explore the predictive significance of TNF-α and/or p38MAPK expression in patients with HCC. Using the Oncomine™ database, it was revealed that TNF-α and/or p38MAPK expression was not significantly associated with overall survival (OS) or disease-free survival (DFS) rates; however, TNF-α and p38MAPK expression levels were positively associated (P<0.05), and high p38MAPK expression was significantly associated with low aspartate aminotransferase levels (P<0.05). Compared with low expression levels of TNF-α and p38MAPK together, high expression of TNF-α alone, p38MAPK alone and TNF-α and p38MAPK together were significantly associated with improved OS and DFS rates (P<0.05). Additionally, multivariate Cox regression models suggested that high expression levels of TNF-α alone, p38MAPK alone, or TNF-α and p38MAPK together in the HCC microenvironment were independent predictive factors for OS and DFS rates (P<0.05). Patients with T1N0M0 HCC with high TNF-α and/or p38MAPK expression had a significantly lower risk of recurrence and mortality compared with patients with low TNF-α and p38MAPK expression. Consequently, TNF-α and p38MAPK could serve as predictive biomarkers or potential therapeutic targets for T1N0M0 HCC treatment.
Collapse
Affiliation(s)
- Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jie Hu
- Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410006, P.R. China
| | - Haoran Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Shun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Weiyu Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Liqun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| |
Collapse
|
|
37
|
Xing X, Yuan H, Sun Y, Ke K, Dong X, Chen H, Liu X, Zhao B, Huang A. ANXA2 Tyr23 and FLNA Ser2152 phosphorylation associate with poor prognosis in hepatic carcinoma revealed by quantitative phosphoproteomics analysis. J Proteomics 2019; 200:111-122. [PMID: 30951906 DOI: 10.1016/j.jprot.2019.03.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 03/15/2019] [Accepted: 03/31/2019] [Indexed: 02/06/2023]
Abstract
Hepatoma is one of the most common malignant tumors, and most patients have very poor prognosis. Early prediction and intervention of the hepatoma recurrence/metastasis are the most effective way to improve the patients' clinical outcomes. Here, we used isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative phospho-proteomics approach to identify biomarkers associated with hepatoma recurrence/metastasis in hepatoma cell lines with increasing metastasis ability. In total, 75 phosphorylated peptides corresponding to 60 phosphoproteins were significantly dysregulated and the participated biological processes of these phosphoproteins were tightly associated with tumor metastasis. Further signaling pathway analysis revealed that key signaling pathways which play crucial roles in cancer metastasis have been significantly over activated in the highly metastatic cells. Furthermore, the phosphorylation of FLNASer2152 and ANXA2Tyr23 were validated to be significantly up regulated in the high-metastatic cells comparing with the low-metastatic cells. By further investigation the clinical significance of the phosphorylation of FLNASer2152 and ANXA2Tyr23 in large-scale clinical samples, revealed that the over phosphorylation of FLNASer2152 and ANXA2Tyr23 were associated with poor prognosis and might be potential prognostic biomarkers for the primary hepatoma. When FLNASer2152 combined with ANXA2Tyr23, it had a better prognostic value for both OS and TTR.
Collapse
Affiliation(s)
- Xiaohua Xing
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350004, People's Republic of China
| | - Hui Yuan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China; The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China
| | - Ying Sun
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Kun Ke
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China; The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China
| | - Xiuqing Dong
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China
| | - Hui Chen
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People's Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350004, People's Republic of China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China.
| | - Aimin Huang
- The School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350004, People's Republic of China.
| |
Collapse
|
|
38
|
FAM83D is associated with gender, AJCC stage, overall survival and disease-free survival in hepatocellular carcinoma. Biosci Rep 2019; 39:BSR20181640. [PMID: 30910840 PMCID: PMC6504662 DOI: 10.1042/bsr20181640] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 02/12/2019] [Accepted: 03/15/2019] [Indexed: 12/24/2022] Open
Abstract
Prognostic significance of family with sequence similarity 83, member D (FAM83D) in hepatocellular carcinoma (HCC) patients has not been well-investigated using Gene Expression Omnibus (GEO) series and TCGA database, we compared FAM83D expression levels between tumor and adjacent tissues, and correlated FAM83D in tumors with outcomes and clinico-pathological features in HCC patients. Validated in GSE33006, GSE45436, GSE84402 and TCGA, FAM83D was significantly overexpressed in tumor tissues than that in adjacent tissues (all P<0.01). FAM83D up-regulation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in HCC patients (Log rank P=0.00583 and P=4.178E-04, respectively). Cox analysis revealed that FAM83D high expression was significantly associated with OS in HCC patients [hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.005-2.063, P=0.047]. Additionally, patients deceased or recurred/progressed had significantly higher FAM83D mRNA levels than those living or disease-free (P=0.0011 and P=0.0238, respectively). FAM83D high expression group had significantly more male patients and advanced American Joint Committee on Cancer (AJCC) stage cases (P=0.048 and P=0.047, respectively). FAM83D mRNA were significantly overexpressed in male (P=0.0193). Compared with patients with AJCC stage I, those with AJCC stage II and stage III-IV had significantly higher FAM83D mRNA levels (P = 0.0346 and P=0.0045, respectively). In conclusion, overexpressed in tumors, FAM83D is associated with gender, AJCC stage, tumor recurrence and survival in HCC.
Collapse
|
|
39
|
Cho W, Jin X, Pang J, Wang Y, Mivechi NF, Moskophidis D. The Molecular Chaperone Heat Shock Protein 70 Controls Liver Cancer Initiation and Progression by Regulating Adaptive DNA Damage and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling Pathways. Mol Cell Biol 2019; 39:e00391-18. [PMID: 30745413 PMCID: PMC6469921 DOI: 10.1128/mcb.00391-18] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 08/21/2018] [Accepted: 02/04/2019] [Indexed: 02/06/2023] Open
Abstract
Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC but also for the development of diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several cochaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, the HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated. Here, we show that genetic ablation of HSP70 markedly impairs HCC initiation and progression by distinct but overlapping pathways. This includes the potentiation of the carcinogen-induced DNA damage response, at the tumor initiation stage, to increase the p53-dependent surveillance response leading to the cell cycle exit or death of genomically damaged differentiated pericentral hepatocytes, and this may also prevent their conversion into more proliferating HCC progenitor cells. Subsequently, activation of a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) negative feedback pathway diminishes oncogenic signals, thereby attenuating premalignant cell transformation and tumor progression. Modulation of HSP70 function may be a strategy for interfering with oncogenic signals driving liver cell transformation and tumor progression, thus providing an opportunity for human cancer control.
Collapse
Affiliation(s)
- Wonkyoung Cho
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Xiongjie Jin
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Junfeng Pang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Yan Wang
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Nahid F Mivechi
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Radiology and Imaging, Augusta University, Augusta, Georgia, USA
| | - Demetrius Moskophidis
- Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Medicine, Augusta University, Augusta, Georgia, USA
| |
Collapse
|
|
40
|
Xiong T, Li J, Chen F, Zhang F. PCAT-1: A Novel Oncogenic Long Non-Coding RNA in Human Cancers. Int J Biol Sci 2019; 15:847-856. [PMID: 30906215 PMCID: PMC6429018 DOI: 10.7150/ijbs.30970] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/17/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides (nts) without obvious protein coding potential. lncRNAs act as multiple roles in biological processes of diseases, especially carcinomas. Prostate cancer associated transcript-1 (PCAT-1) is an oncogenic lncRNA that identified by RNA-Sequence in prostate cancer. High expression of PCAT-1 is observed in different types of cancers, including prostate cancer, colorectal cancer, hepatocellular cancer and gastric cancer. High expressed PCAT-1 is correlated with poor overall survival. Furthermore, PCAT-1 regulates cancer cell proliferation, apoptosis, migration and invasion. Additionally, PCAT-1 is involved in EMT and Wnt/β-catenin-signaling pathway. In this review, we focus on the implication of PCAT-1 in human cancers.
Collapse
Affiliation(s)
| | | | - Fangfang Chen
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen 518036
| | - Fangting Zhang
- The Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen 518036
| |
Collapse
|
|
41
|
Homeostatic Model Assessment of Insulin Resistance for Predicting the Recurrence of Hepatocellular Carcinoma after Curative Treatment. Int J Mol Sci 2019; 20:ijms20030605. [PMID: 30704150 PMCID: PMC6387449 DOI: 10.3390/ijms20030605] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 01/18/2019] [Accepted: 01/29/2019] [Indexed: 02/07/2023] Open
Abstract
Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the impact of the disorder of glucose metabolism on the recurrence of HCC after curative treatment. Two hundred and eleven patients with HCC who received curative treatment in our hospital from 2006 to 2017 were enrolled in this study. Recurrence-free survival was estimated using the Kaplan–Meier method, and the differences between the groups partitioned by the presence or absence of DM and the values of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fasting immunoreactive insulin (FIRI), and homeostasis model assessment-insulin resistance (HOMA-IR) were evaluated using the log-rank test. There were no significant differences in the recurrence-free survival rate between the patients with and without DM (p = 0.144), higher and lower levels of HbA1c (≥6.5 and <6.5%, respectively; p = 0.509), FPG (≥126 and <126 mg/dL, respectively; p = 0.143), and FIRI (≥10 and <10 μU/mL, respectively; p = 0.248). However, the higher HOMA-IR group (≥2.3) had HCC recurrence significantly earlier than the lower HOMA-IR group (<2.3, p = 0.013). Moreover, there was a significant difference between the higher and lower HOMA-IR groups without DM (p = 0.009), and there was no significant difference between those groups with DM (p = 0.759). A higher HOMA-IR level, particularly in non-diabetic patients, was a significant predictor for HCC recurrence after curative treatment.
Collapse
|
|
42
|
Liu ZZ, Yan LN, Dong CN, Ma N, Yuan MN, Zhou J, Gao P. Cytochrome P450 family members are associated with fast-growing hepatocellular carcinoma and patient survival: An integrated analysis of gene expression profiles. Saudi J Gastroenterol 2019; 25:167-175. [PMID: 30971588 PMCID: PMC6526731 DOI: 10.4103/sjg.sjg_290_18] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. Although many molecular tools have been developed to assist in stratification and prediction of patients by using microarray analysis, the classification and prediction are still improvable because the high-through microarray contains a large amount of information. Meanwhile, gene expression patterns and their prognostic value for HCC have not been systematically investigated. In order to explore new molecular diagnostic and prognostic biomarkers, the gene expression profiles between HCCs and adjacent nontumor tissues were systematically analyzed in the present study. MATERIALS AND METHODS In this study, gene expression profiles were obtained by repurposing five Gene Expression Omnibus databases. Differentially expressed genes were identified by using robust rank aggregation method. Three datasets (GSE14520, GSE36376, and GSE54236) were used to validate the associations between cytochrome P450 (CYP) family genes and HCC. GSE14520 was used as the training set. GSE36376 and GSE54236 were considered as the testing sets. RESULTS From the training set, a four-CYP gene signature was constructed to discriminate between HCC and nontumor tissues with an area under curve (AUC) of 0.991. Accuracy of this four-gene signature was validated in two testing sets (AUCs for them were 0.973 and 0.852, respectively). Moreover, this gene signature had a good performance to make a distinction between fast-growing HCC and slow-growing HCC (AUC = 0.898), especially for its high sensitivity of 95%. At last, CYP2C8 was identified as an independent risk factor of recurrence-free survival (hazard ratio [HR] =0.865, 95% confidence interval [CI], 0.754-0.992, P = 0.038) and overall survival (HR = 0.849; 95% CI, 0.716-0.995, P = 0.033). CONCLUSIONS In summary, our results confirmed for the first time that a four-CYP gene (CYP1A2, CYP2E1, CYP2A7, and PTGIS) signature is associated with fast-growing HCC, and CYP2C8 is associated with patient survival. Our findings could help to identify HCC patients at high risk of rapid growth and recurrence.
Collapse
Affiliation(s)
- Zhao-Zhen Liu
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Li-Na Yan
- Hebei Province Key Laboratory of Environment and Human Health, Hebei, China,Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Hebei, China
| | - Chun-Nan Dong
- Department of Pathogenic Biology, Hebei Medical University, Hebei, China
| | - Ning Ma
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Mei-Na Yuan
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Jin Zhou
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China
| | - Ping Gao
- Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, Hebei, China,Hebei Province Key Laboratory of Environment and Human Health, Hebei, China,Address for correspondence: Dr. Ping Gao, Department of Social Medicine and Health Care Management, School of Public Health, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang, 050017, Hebei Province, China. E-mail:
| |
Collapse
|
|
43
|
Zhang M, Zhang S, Yang Z, Hu J, Hu W, Sun P, Wu L, Han B. Association between the expression levels of IL-6 and IL-6R in the hepatocellular carcinoma microenvironment and postoperative recurrence. Oncol Lett 2018; 16:7158-7165. [PMID: 30546452 PMCID: PMC6256737 DOI: 10.3892/ol.2018.9557] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022] Open
Abstract
The tumor microenvironment of hepatocellular carcinoma (HCC) is a complex system, involving mutual promotion and inhibition between cells and molecules. It results in alterations to inflammatory-associated factors, including a decrease in interleukin (IL)-2 and an increase in tumor necrosis factor, together with a characteristic elevation of IL-6. Following the synthesis and release of IL-6, HCC is stimulated through IL-6 binding to the IL-6 receptor (IL-6R). In the present study, immunohistochemistry was performed to investigate the expression levels of IL-6 and IL-6R in 92 patients with HCC, and the association between IL-6/IL-6R expression levels and tumor recurrence was examined. Notably increased expression levels of IL-6 and IL-6R were observed in the HCC microenvironment, and recurrence occurred earlier in patients with high IL-6/IL-6R expression levels compared with those with low expression levels (P<0.05). However, there was no significant difference in overall survival between patients in the two groups (P>0.05). Platelet levels <100×109/l, tumor-node-metastasis stage IIIa and high expression levels of IL-6/IL-6R were independent risk factors for postoperative recurrence (P<0.05). The present study proposed that high IL-6 and IL-6R expression in the HCC microenvironment promotes postoperative tumor recurrence, suggesting that these may be potential predictors of recurrence, and may be used as possible therapeutic targets to enhance the long-term survival of patients.
Collapse
Affiliation(s)
- Mao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Shun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Zhenjie Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jie Hu
- Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410006, P.R. China
| | - Weiyu Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Peng Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Liqun Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bing Han
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| |
Collapse
|
|
44
|
Liao M, Chen P, Liao Y, Li J, Yao W, Sun T, Liao W, Su L. Preoperative high-sensitivity C-reactive protein to lymphocyte ratio index plays a vital role in the prognosis of hepatocellular carcinoma after surgical resection. Onco Targets Ther 2018; 11:5591-5600. [PMID: 30237725 PMCID: PMC6135434 DOI: 10.2147/ott.s167857] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background At present, the predictive ability of the prognostic indicator of hepatocellular carcinoma (HCC) is still limited. This study aims to analyze the relationship between the preoperative high-sensitivity C-reactive protein to lymphocyte ratio (HCLR) and the clinicopathologic characteristics of HCC. Patients and methods A total of 229 HCC patients undergoing surgical resection were retrospectively analyzed. The majority of the patients (132/229) had tumors larger than 5 cm, and 45 out of 229 had more than one tumor focus. Receiver operating characteristic curve analysis was used to decide the cutoff value of HCLR. The overall survival (OS) and progression-free survival (PFS) rates were evaluated by adopting the Kaplan–Meier method. Results The cutoff value of HCLR for the best discrimination of HCC prognosis was 1.3 with a sensitivity of 75.5% and a specificity of 71.8%. The area under the receiver operating characteristic curve was 0.791 (95% CI, 0.731–0.840). Preoperative HCLR at a high level (>1.3) was positively correlated with large tumor size, TNM stage, microvascular invasion, and recurrence. The mean OS and PFS in patients with HCLR >1.3 were significantly shorter than in those with HCLR ≤1.3. Univariate and multivariate analyses revealed the HCLR was an independent predictor of OS and PFS. Conclusion HCLR was an important independent predictor of dismal prognosis in HCC patients and can be used as a sensitive indicator for the dynamic monitoring of postoperative patients.
Collapse
Affiliation(s)
- Minjun Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, , .,Guangxi Medical University, Nanning, Guangxi, People's Republic of China,
| | - Pu Chen
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, ,
| | - Yan Liao
- Disease Prevention and Control Center of Guilin, Guilin, Guangxi, People's Republic of China
| | - Jun Li
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, ,
| | - Wenmin Yao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, ,
| | - Tian Sun
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, ,
| | - Weijia Liao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China, ,
| | - Lili Su
- Department of Clinical Laboratory, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, People's Republic of China
| |
Collapse
|
|
45
|
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.
Collapse
Affiliation(s)
- Ying Fu
- Laboratory of Molecular Biology, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
| | - Fung-Lung Chung
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA
| |
Collapse
|
|
46
|
Bai F, Zhou H, Ma M, Guan C, Lyu J, Meng QH. A novel RNA sequencing-based miRNA signature predicts with recurrence and outcome of hepatocellular carcinoma. Mol Oncol 2018; 12:1125-1137. [PMID: 29719937 PMCID: PMC6026871 DOI: 10.1002/1878-0261.12315] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the second leading cause of cancer-related deaths worldwide. Given that the rate of HCC recurrence 5 years after liver resection is as high as 70%, patient with HCC typically has a poor outcome. A biomarker or set of biomarkers that could predict disease recurrence would have a substantial clinical impact, allowing earlier detection of recurrence and more effective treatment. With the aim of identifying a new microRNA (miRNA) signature associated with HCC recurrence, we analyzed data on 306 patients with HCC for whom both miRNA expression profiles and complete clinical information were available from The Cancer Genome Atlas database. Through this analysis, we identified a six-miRNA signature that could effectively predict patients' recurrence risk; the high-risk and low-risk groups had significantly different recurrence-free survival rates. Time-dependent receiver operating characteristic analysis indicated that this signature had a good predictive performance. Multivariable Cox regression and stratified analyses demonstrated that the six-miRNA signature was independent of other clinical features. Functional enrichment analysis of the gene targets of the six prognostic miRNA indicated enrichment mainly in cancer-related pathways and important cell biological processes. Our results support use of this six-miRNA signature as an independent factor for predicting recurrence and outcome of patients with HCC.
Collapse
Affiliation(s)
- Fumao Bai
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Mengni Ma
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Chen Guan
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, China
| | - Qing H Meng
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
47
|
Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid. Proc Natl Acad Sci U S A 2018; 115:4969-4974. [PMID: 29686061 PMCID: PMC5949003 DOI: 10.1073/pnas.1802279115] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer, partly because of its high rate of recurrence, which is caused by the presence of liver cancer stem cells (CSCs). Here, using a selective chemopreventive agent, acyclic retinoid (ACR), as a bioprobe, we identified MYCN, which is mostly recognized as an oncogene in neuroblastoma, as a therapeutic target of ACR for HCC through a selective deletion of MYCN+ liver CSCs. We also demonstrated that the expression of MYCN in HCC served as a prognostic biomarker and positively correlated with recurrence of de novo HCC after curative treatment. Our study highlighted MYCN as a biomarker and therapeutic target in drug discovery for screening chemopreventive agents against the recurrence of HCC. Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix–loop–helix–zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/β-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM− cells. In a long-term (>10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.
Collapse
|
|
48
|
Zhong Y, Huang H, Chen M, Huang J, Wu Q, Yan GR, Chen D. POU2F1 over-expression correlates with poor prognoses and promotes cell growth and epithelial-to-mesenchymal transition in hepatocellular carcinoma. Oncotarget 2018; 8:44082-44095. [PMID: 28489585 PMCID: PMC5546464 DOI: 10.18632/oncotarget.17296] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 04/03/2017] [Indexed: 12/31/2022] Open
Abstract
Despite recent efforts to understand activities of POU domain class 2 transcription factor 1 (POU2F1), little is known about the roles of POU2F1 in hepatocellular carcinoma (HCC) tumorigenesis and its correlation with any clinicopathological feature of HCC. In this study, we found that POU2F1 was significantly up-regulated in HCC specimens compared with adjacent non-cancerous liver specimens. The high POU2F1 protein expression level positively correlated with large tumor size, high histological grade, tumor metastasis and advanced clinical stage, and HCC patients with high POU2F1 levels exhibited poor prognoses. We further demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, epithelial-to-mesenchymal transition (EMT), migration and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. POU2F1 induced the expression of Twist1, Snai1, Snai2 and ZEB1 genes which are involved in the regulation of EMT. Furthermore, POU2F1 was up-regulated by AKT pathway in HCC, and POU2F1 over-expression reversed the inhibition of malignant phenotypes induced by AKT knock-down, indicating POU2F1 is a key down-stream effector of AKT pathway. Collectively, our results indicate that POU2F1 over-expression is positively associated with aggressive phenotypes and poor survival in patients with HCC, and POU2F1 regulated by AKT pathway promotes HCC aggressive phenotypes by regulating the transcription of EMT genes. POU2F1 may be employed as a new prognostic factor and therapeutic target for HCC.
Collapse
Affiliation(s)
- Yonghao Zhong
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongyang Huang
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Min Chen
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jinzhou Huang
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingxia Wu
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guang-Rong Yan
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, China
| | - De Chen
- Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
49
|
Wang X, Wang Y, Zhang Q, Zhuang H, Chen B. MAP Kinase-Interacting Kinase 1 Promotes Proliferation and Invasion of Hepatocellular Carcinoma and Is an Unfavorable Prognostic Biomarker. Med Sci Monit 2018; 24:1759-1767. [PMID: 29576605 PMCID: PMC5885772 DOI: 10.12659/msm.909012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) accounts for one of the most prevalent tumor types in the world. The MAP kinase-interacting kinase 1 (MNK1) functions downstream of MAP kinases such as p38 and ERK, and its potential role in cancer development is being uncovered. The aim of this study was to investigate the expression and function of MNK1 in HCC. Material/Methods Immunohistochemical staining and quantitative PCR were performed to explore the expression of MNK1 in both HCC tissues and adjacent normal liver tissues. Chi-square test, univariate analysis, and multivariate analysis were conducted to statistically evaluate clinical significance of MNK1 in HCC. Proliferation, migration, and invasion capacities of HCC cells were assessed after overexpressing or silencing MNK1. Results Both the RNA and protein levels of MNK1 were upregulated in HCC tissues compared to normal liver tissues. High expression of MNK1 was correlated with advanced tumor stage and poor overall survival. Moreover, MNK1 was identified as a novel independent prognostic factor for HCC patients. Cellular studies showed that MNK1 can enhance the proliferation, migration, and invasion capacities of HCC cells, thereby promoting tumor progression. Conclusions High expression of MNK1 is frequent in HCC tissues, which promotes tumor proliferation and invasion, and is correlated with a poor overall survival. Targeting MNK1 may be a novel direction for the drug development of HCC therapy.
Collapse
Affiliation(s)
- Xujing Wang
- Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China (mainland)
| | - Yongkun Wang
- Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China (mainland)
| | - Qiqi Zhang
- Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China (mainland)
| | - Huiren Zhuang
- Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China (mainland)
| | - Bo Chen
- Department of Hepatopancreatobiliary Surgery, East Hospital Affiliated to Tongji University in Shanghai, Shanghai, China (mainland)
| |
Collapse
|
|
50
|
Liu S, Miao C, Liu J, Wang C, Lu X. Four differentially methylated gene pairs to predict the prognosis for early stage hepatocellular carcinoma patients. J Cell Physiol 2018; 233:6583-6590. [DOI: 10.1002/jcp.26256] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 11/07/2017] [Indexed: 02/03/2023]
Affiliation(s)
- Shaoguang Liu
- Department of Emergency SurgeryGansu Provincial HospitalGansuChina
| | - Changfeng Miao
- Department of General SurgeryGansu Provincial HospitalGansuChina
| | - Juan Liu
- Operating Room, Huai'an Second People's HospitalThe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'anChina
| | - Chang‐Cheng Wang
- Department of GastroenterologyHuai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'anJiangsuChina
| | - Xiao‐Jie Lu
- Liver Transplantation CenterThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| |
Collapse
|