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Ding X, Shi J, Lei Z, Wang G, Fu C, Su X, Zhu G. FOXM1 promotes malignant biological behavior and metabolic reprogramming by targeting SPINK1 in hepatocellular carcinoma and affecting the p53 pathway. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167673. [PMID: 39828047 DOI: 10.1016/j.bbadis.2025.167673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/24/2024] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
This study investigates the role of SPINK1 in liver cancer and its regulatory relationship with FOXM1. Using differential gene analysis in the GEO database, SPINK1 was identified as overexpressed in liver cancer tissues and associated with poor prognosis, confirmed via PCR. Functional assays demonstrated that SPINK1 knockdown reduced proliferation, migration, and invasion in liver cancer cells, while promoting apoptosis. In vivo experiments revealed that SPINK1 knockdown inhibited tumor growth, decreased Ki-67 and N-cadherin levels, increased E-cadherin levels, and suppressed lung metastasis. Analysis of upstream factors indicated that FOXM1 binds to the SPINK1 promoter, as validated by dual-luciferase and ChIP assays, thereby promoting SPINK1 transcription. TCGA database analysis and clinical tissue validation showed that FOXM1 expression correlates with poor prognosis in liver cancer. Functional studies demonstrated that FOXM1 knockdown suppressed liver cancer progression, while SPINK1 overexpression reversed these effects. KEGG enrichment analysis identified the p53 pathway as a key downstream target of SPINK1, and Western blotting confirmed its role in modulating p53 pathway activity. These findings reveal a critical FOXM1-SPINK1 axis in liver cancer progression. FOXM1 directly promotes SPINK1 transcription, enhancing tumor cell proliferation and metastasis while regulating the p53 pathway. Targeting this axis could provide a potential therapeutic approach for liver cancer.
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Affiliation(s)
- Xu Ding
- School of Medicine, Southeast University, Naanjing 210009, Jiangsu, PR China
| | - Jinjun Shi
- Department of Ultrasound, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu, PR China
| | - Zhengqing Lei
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing 210009, Jiangsu, PR China
| | - Guoqing Wang
- Department of Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, PR China
| | - Chenchun Fu
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, PR China
| | - Xiangyu Su
- Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, PR China.
| | - Guangyu Zhu
- Center of Interventional Radiology & Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu, PR China.
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Deng G, Ren JK, Wang HT, Deng L, Chen ZB, Fan YW, Tang YJ, Zhang T, Tang D. Tumor burden score dictates prognosis of patients with combined hepatocellular cholangiocarcinoma undergoing hepatectomy. Front Oncol 2023; 12:977111. [PMID: 36755864 PMCID: PMC9900097 DOI: 10.3389/fonc.2022.977111] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 12/28/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The prognostic value of the tumor burden score (TBS) in patients with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unknown. This study aimed to investigate the impact of TBS on long-term outcomes after surgery. METHODS Patients who underwent radical-intent resection between June 2013 and December 2019 were retrospectively reviewed. Kaplan-Meier curves were used to analyze patient survival, and disease-free survival (DFS) and overall survival (OS) were examined in relation to TBS. RESULTS A total of 178 patients were included in this study, with 119 in the training cohort and 59 in the validation cohort. Kaplan-Meier curves showed that TBS was a strong prognostic indicator in patients with cHCC-CCA. Elevated TBS was associated with poorer DFS and OS (both P-value < 0.001) and was identified as an independent prognostic indicator. In addition, the prognostic value of TBS outperformed tumor size and number alone, microvascular invasion, and lymph node invasion. The prognostic significance of TBS was confirmed by the internal validation cohort. CONCLUSIONS The present study suggested the significance of tumor morphology in assessing the prognosis of patients with cHCC-CCA who undergoing curative resection. The TBS is a promising prognostic index in patients with cHCC-CCA. Elevated TBS was related to a lower long-term survival rate and was identified as an independent risk factor for poor DFS and OS. Further research is needed to verify our results.
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Affiliation(s)
- Gang Deng
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jun-kai Ren
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hai-tao Wang
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Liang Deng
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zu-bing Chen
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - You-wen Fan
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ya-jun Tang
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tong Zhang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Di Tang
- Department of General Surgery, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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Zhang G, Chen BW, Yang XB, Wang HY, Yang X, Xie FC, Chen XQ, Yu LX, Shi J, Lu YY, Zhao HT. Prognostic analysis of patients with combined hepatocellular-cholangiocarcinoma after radical resection: A retrospective multicenter cohort study. World J Gastroenterol 2022; 28:5968-5981. [PMID: 36405111 PMCID: PMC9669829 DOI: 10.3748/wjg.v28.i41.5968] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/24/2022] [Accepted: 10/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a form of rare primary liver cancer that combines intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma.
AIM To investigate overall survival (OS) and recurrence-free survival (RFS) after radical resection in patients with cHCC-CCA, and the clinicopathological factors affecting prognosis in two center hospitals of China.
METHODS We reviewed consecutive patients with cHCC-CCA who received radical resection between January 2005 and September 2021 at Peking Union Medical College and the 5th Medical Center of the PLA General Hospital retrospectively. Regular follow-up and clinicopathological characteristics were systematic collected for baseline and prognostic analysis.
RESULTS Our study included 95 patients who received radical resection. The majority of these patients were male and 82.7% of these patients were infected with HBV. The mean tumor size was 4.5 cm, and approximately 40% of patients had more than one lesion. The median OS was 26.8 (95%CI: 18.5-43.0) mo, and the median RFS was 7.27 (95%CI: 5.83-10.3) mo. Independent predictors of OS were CA19-9 ≥ 37 U/mL (HR = 8.68, P = 0.002), Child-Pugh score > 5 (HR = 5.52, P = 0.027), tumor number > 1 (HR = 30.85, P = 0.002), tumor size and transarterial chemoembolization (TACE) after surgery (HR = 0.2, P = 0.005).
CONCLUSION The overall postoperative survival of cHCC-CCA patients is poor, and most patients experience relapse within a short period of time after surgery. Preoperative tumor biomarker (CA19-9, alpha-fetoprotein) levels, tumor size, and Child-Pugh score can significantly affect OS. Adjuvant TACE after surgery prolongs RFS, suggesting that TACE is a possible option for postoperative adjuvant therapy in patients with cHCC-CCA.
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Affiliation(s)
- Ge Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bo-Wen Chen
- 302 Clinical Medical School, Peking University, Beijing 100039, China
- Senior Department of Hepatology, The 5th Medical Center of the PLA General Hospital, Beijing 100039, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Huai-Yuan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xu Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Fu-Cun Xie
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiang-Qi Chen
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ling-Xiang Yu
- Senior Department of Hepatology, The 5th Medical Center of the PLA General Hospital, Beijing 100039, China
| | - Jie Shi
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yin-Ying Lu
- 302 Clinical Medical School, Peking University, Beijing 100039, China
- Senior Department of Hepatology, The 5th Medical Center of the PLA General Hospital, Beijing 100039, China
- Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, Guangdong Province, China
| | - Hai-Tao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Xu J, Li S, Feng Y, Zhang J, Peng Y, Wang X, Wang H. The Fibrinogen/Albumin Ratio Index as an Independent Prognostic Biomarker for Patients with Combined Hepatocellular Cholangiocarcinoma After Surgery. Cancer Manag Res 2022; 14:1795-1806. [PMID: 35637941 PMCID: PMC9143788 DOI: 10.2147/cmar.s361462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/07/2022] [Indexed: 12/13/2022] Open
Abstract
Purpose The fibrinogen/albumin ratio (FAR) is increasingly considered as a potential biomarker for predicting prognosis in various malignant tumors, whereas the value of the FAR in predicting the recurrence-free survival (RFS) in patients with combined hepatocellular cholangiocarcinoma (cHCC-CCA) after surgery has not been studied. Patients and Methods A total of 104 patients with surgical-pathologically proved cHCC-CCA were retrospectively analyzed. The best cut-off value of the FAR was calculated via receiver operating characteristic (ROC) curve analysis, and the cohort was then divided into two groups as high-FAR (H-FAR) group and low-FAR (L-FAR) group. The correlation between the preoperative FAR and clinicopathological characteristics was analyzed. Uni- and multi-variable analyses for RFS were evaluated using a Cox proportional hazards model to verify the predictive value of FAR on the RFS of cHCC-CCA. Additionally, a novel clinical nomogram based on FAR was developed to preoperatively predict the RFS of HCC-CCA. The C-index and calibration were conducted to evaluate the performance of the developed nomogram. Results According to the cut-off value of the FAR, the patients were grouped into the H-FARI (>0.075) and L-FARI (≤0.075) groups. FAR was significantly correlated with several clinical-pathological features, including age, cirrhosis, AFP, CA19-9, BCLC staging, NLR, and PLR. In the multi-variate analysis, FAR, cirrhosis and tumor size were independent prognostic predictors for poor RFS in cHCC-CCA patients after surgery. Moreover, the clinical nomogram based on FAR was constructed, showing well-predictive accuracy. Conclusion The preoperative FAR is a convenient and feasible serum biomarker for predicting the RFS of cHCC-CCA after surgery. Such developed FAR-based nomogram integrating tumor size and cirrhosis could be served as a feasible and convenient tool to assist the decision-making of clinical strategy.
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Affiliation(s)
- Jiake Xu
- Department of Gastroenterology, Kunshan Second People’s Hospital, Kunshan, People’s Republic of China
| | - Shaochun Li
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
| | - Ye Feng
- Department of Gastroenterology, Kunshan Second People’s Hospital, Kunshan, People’s Republic of China
| | - Jie Zhang
- Department of Gastroenterology, Kunshan Second People’s Hospital, Kunshan, People’s Republic of China
| | - Youduo Peng
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
| | - Xiaohong Wang
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
| | - Hongwei Wang
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China
- Correspondence: Hongwei Wang, Tel +86 15021133649, Email
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Combined Hepatocellular-Cholangiocarcinoma: What the Multidisciplinary Team Should Know. Diagnostics (Basel) 2022; 12:diagnostics12040890. [PMID: 35453938 PMCID: PMC9026907 DOI: 10.3390/diagnostics12040890] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/01/2022] [Accepted: 04/01/2022] [Indexed: 12/10/2022] Open
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare type of primary liver malignancy. Among the risk factors, hepatitis B and hepatitis C virus infections, cirrhosis, and male gender are widely reported. The clinical appearance of cHCC-CCA is similar to that of HCC and iCCA and it is usually silent until advanced states, causing a delay of diagnosis. Diagnosis is mainly based on histology from biopsies or surgical specimens. Correct pre-surgical diagnosis during imaging studies is very problematic and is due to the heterogeneous characteristics of the lesion in imaging, with overlapping features of HCC and CCA. The predominant histological subtype within the lesion establishes the predominant imaging findings. Therefore, in this scenario, the radiological findings characteristic of HCC show an overlap with those of CCA. Since cHCC-CCAs are prevalent in patients at high risk of HCC and there is a risk that these may mimic HCC, it is currently difficult to see a non-invasive diagnosis of HCC. Surgery is the only curative treatment of HCC-CCA. The role of liver transplantation (LT) in the treatment of cHCC-CCA remains controversial, as is the role of ablative or systemic therapies in the treatment of this tumour. These lesions still remain challenging, both in diagnosis and in the treatment phase. Therefore, a pre-treatment imaging diagnosis is essential, as well as the identification of prognostic factors that could stratify the risk of recurrence and the most adequate therapy according to patient characteristics.
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The Prognostic Role of Glutathione and Its Related Antioxidant Enzymes in the Recurrence of Hepatocellular Carcinoma. Nutrients 2021; 13:nu13114071. [PMID: 34836325 PMCID: PMC8622054 DOI: 10.3390/nu13114071] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/04/2021] [Accepted: 11/11/2021] [Indexed: 12/15/2022] Open
Abstract
The imbalance of high oxidative stress and low antioxidant capacities is thought to be a significant cause of the development and progression of hepatocellular carcinoma (HCC). However, the impact of oxidative stress, glutathione (GSH), and its related antioxidant enzymes on the recurrence of HCC has not been investigated. The purpose of this study was to compare the changes to oxidative stress and GSH-related antioxidant capacities before and after tumor resection in patients with HCC recurrence and non-recurrence. We also evaluated the prognostic significance of GSH and its related enzymes in HCC recurrence. This was a cross-sectional and follow-up study. Ninety-two HCC patients who were going to receive tumor resection were recruited. We followed patients' recurrence and survival status until the end of the study, and then assigned patients into the recurrent or the non-recurrent group. The tumor recurrence rate was 52.2% during the median follow-up period of 3.0 years. Patients had significantly lower plasma malondialdehyde level, but significantly or slightly higher levels of GSH, glutathione disulfide, trolox equivalent antioxidant capacity, glutathione peroxidase (GPx), and glutathione reductase (GR) activities after tumor resection compared to the respective levels before tumor resection in both recurrent and non-recurrent groups. GSH level in HCC tissue was significantly higher than that in adjacent normal tissue in both recurrent and non-recurrent patients. Decreased plasma GPx (HR = 0.995, p = 0.01) and GR (HR = 0.98, p = 0.04) activities before tumor resection, and the increased change of GPx (post-pre-resection) (HR = 1.004, p = 0.03) activity were significantly associated with the recurrence of HCC. These findings suggest there might be a possible application of GPx or GR as therapeutic targets for reducing HCC recurrence.
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