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Lu F, Ott C, Bista P, Lu X. Three-Dimensional Structure of Novel Liver Cancer Biomarker Liver Cancer-Specific Serine Protease Inhibitor Kazal (LC-SPIK) and Its Performance in Clinical Diagnosis of Hepatocellular Carcinoma (HCC). Diagnostics (Basel) 2024; 14:725. [PMID: 38611638 PMCID: PMC11011646 DOI: 10.3390/diagnostics14070725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
LC-SPIK is a liver cancer-specific isoform of Serine Protease Inhibitor Kazal and has been proposed as a new biomarker for the detection of HCC given its unique 3D structure, which differs from normal pancreatic SPIK. An ELISA technology based on its unique structure was developed to use LC-SPIK as an effective biomarker for the clinical diagnosis of HCC. AFP, the most widely used biomarker for HCC surveillance currently, suffers from poor clinical performance, especially in the detection of early-stage HCC. In one case-control study, which included 164 HCC patients and 324 controls, LC-SPIK had an AUC of 0.87 compared to only 0.70 for AFP in distinguishing HCC from liver disease controls (cirrhosis, HBV/HCV). LC-SPIK also performed significantly better than AFP for the 81 patients with early-stage HCC (BCLC stage 0 and A), with an AUC of 0.85 compared to only 0.61 for AFP. Cirrhosis is the major risk factor for HCC; about 80% of patients with newly diagnosed HCC have preexisting cirrhosis. LC-SPIK's clinical performance was also studied in HCC patients with viral and non-viral cirrhosis, including cirrhosis caused by metabolic dysfunction-associated steatotic liver disease (MASLD) and alcoholic liver disease (ALD). In a total of 163 viral cirrhosis patients with 93 HCC patients (50 early-stage), LC-SPIK had an AUC of 0.85, while AFP had an AUC of 0.70. For patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while AFP had an AUC of only 0.60. For 120 patients with nonviral cirrhosis, including 62 HCC (23 early-stage) patients, LC-SPIK had an AUC of 0.84, while AFP had an AUC of only 0.72. For the 23 patients with early-stage HCC, LC-SPIK had a similar AUC of 0.83, while the AUC for AFP decreased to 0.65. All these results suggest that LC-SPIK exhibits significantly better performance in the detection of HCC than AFP in all etiologies of liver diseases. In addition, LC-SPIK accurately detected the presence of HCC in 71-91% of HCC patients with false-negative AFP test results in viral-associated HCC and non-viral-associated HCC.
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Affiliation(s)
| | | | | | - Xuanyong Lu
- ImCare Biotech, 3805 Old Easton Road, Doylestown, PA 18902, USA; (F.L.); (C.O.); (P.B.)
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Bo Z, Chen B, Yang Y, Yao F, Mao Y, Yao J, Yang J, He Q, Zhao Z, Shi X, Chen J, Yu Z, Yang Y, Wang Y, Chen G. Machine learning radiomics to predict the early recurrence of intrahepatic cholangiocarcinoma after curative resection: A multicentre cohort study. Eur J Nucl Med Mol Imaging 2023; 50:2501-2513. [PMID: 36922449 DOI: 10.1007/s00259-023-06184-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/28/2023] [Indexed: 03/18/2023]
Abstract
PURPOSE Postoperative early recurrence (ER) leads to a poor prognosis for intrahepatic cholangiocarcinoma (ICC). We aimed to develop machine learning (ML) radiomics models to predict ER in ICC after curative resection. METHODS Patients with ICC undergoing curative surgery from three institutions were retrospectively recruited and assigned to training and external validation cohorts. Preoperative arterial and venous phase contrast-enhanced computed tomography (CECT) images were acquired and segmented. Radiomics features were extracted and ranked through their importance. Univariate and multivariate logistic regression analysis was used to identify clinical characteristics. Various ML algorithms were used to construct radiomics-based models, and the predictive performance was evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS 127 patients were included for analysis: 90 patients in the training set and 37 patients in the validation set. Ninety-two patients (72.4%) experienced recurrence, including 71 patients exhibiting ER. Male sex, microvascular invasion, TNM stage, and serum CA19-9 were identified as independent risk factors for ER, with the corresponding clinical model having a poor predictive performance (AUC of 0.685). Fifty-seven differential radiomics features were identified, and the 10 most important features were utilized for modelling. Seven ML radiomics models were developed with a mean AUC of 0.87 ± 0.02, higher than the clinical model. Furthermore, the clinical-radiomics models showed similar predictive performance to the radiomics models (AUC of 0.87 ± 0.03). CONCLUSION ML radiomics models based on CECT are valuable in predicting ER in ICC.
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Affiliation(s)
- Zhiyuan Bo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bo Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Yang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Fei Yao
- Department of Radiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yicheng Mao
- Department of Optometry and Ophthalmology College, Wenzhou Medical University, Wenzhou, China
| | - Jiangqiao Yao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinhuan Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qikuan He
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhengxiao Zhao
- Department of Oncology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xintong Shi
- Department of Hepatobiliary Surgery, the Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jicai Chen
- Department of General Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhengping Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yunjun Yang
- Department of Radiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Yi Wang
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
| | - Gang Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Yuan ZB, Fang HB, Feng QK, Li T, Li J. Prognostic factors of recurrent intrahepatic cholangiocarcinoma after hepatectomy: A retrospective study. World J Gastroenterol 2022; 28:1574-1587. [PMID: 35582131 PMCID: PMC9048463 DOI: 10.3748/wjg.v28.i15.1574] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/18/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumour. Hepatectomy is an effective treatment for early ICC, but postoperative recurrence greatly affects patient survival. Studies on recurrent ICC after hepatectomy are lacking.
AIM To investigate the clinical characteristics of patients with recurrent ICC after hepatectomy, analyse prognostic factors and explore diagnosis and treatment strategies.
METHODS A retrospective analysis was performed on all ICC patients undergoing hepatectomy from January 2013 to August 2021. Patients with postoperative recurrence were selected according to the inclusion and exclusion criteria. Cumulative overall survival was plotted by the Kaplan-Meier method, and differences were assessed by univariate survival analysis using the log-rank test. Multivariate analysis of cumulative survival was performed using the Cox proportional risk model.
RESULTS During the 8-year study period, 103 patients underwent ICC-related hepatectomy, and 54 exhibited postoperative recurrence. The median disease-free survival (DFS) was 6 mo, the median overall survival (OS) was 9 mo, and the cumulative OS rates at 1, 2 and 3 years after the operation were 40.7%, 14.8% and 7.4%, respectively. The median OS after recurrence was 4 mo, and the cumulative OS rates at 1, 2 and 3 years after recurrence were 16.1%, 6.7% and 3.4%, respectively. Multivariate analysis showed that alcohol consumption [hazard ratio (HR) = 4.64, 95% confidence interval (CI): 1.53-14.04, P = 0.007] and DFS < 6 mo (HR = 3.47, 95%CI: 1.59-7.60, P = 0.002) were independent risk factors for the cumulative survival of patients with recurrence, while treatment after recurrence (HR = 0.21, 95%CI: 0.08-0.55, P = 0.001) was an independent protective factor. The median OS time of patients receiving multimodality therapy after recurrence of ICC was 7 mo, which was significantly higher than that of patients receiving only local therapy (3 mo), patients receiving systematic therapy (4 mo) and patients receiving the best supportive therapy (1 mo). Patients with recurrent ICC who received multimodality therapy had a significantly better long-term survival after recurrence than those who did not (P = 0.026).
CONCLUSION The prognosis of patients with recurrence after ICC-related hepatectomy is poor. Alcohol consumption and DFS < 6 mo are independent risk factors in terms of the cumulative survival of patients with recurrence, while treatment after recurrence is an independent protective factor. Multimodality therapy can effectively improve the prognosis of patients.
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Affiliation(s)
- Zi-Bo Yuan
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Henan Research Centre for Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hong-Bo Fang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Henan Research Centre for Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Quan-Kai Feng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Henan Research Centre for Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Tao Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jie Li
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Henan Research Centre for Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Kojima T, Umeda Y, Fuji T, Niguma T, Sato D, Endo Y, Sui K, Inagaki M, Oishi M, Ota T, Hioki K, Matsuda T, Aoki H, Hirai R, Kimura M, Yagi T, Fujiwara T. Efficacy of surgical management for recurrent intrahepatic cholangiocarcinoma: A multi-institutional study by the Okayama Study Group of HBP surgery. PLoS One 2020; 15:e0238392. [PMID: 32881910 PMCID: PMC7470360 DOI: 10.1371/journal.pone.0238392] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/14/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The prognosis of intrahepatic cholangiocarcinoma (ICC) has been poor, because of the high recurrence rate even after curative surgery. This study aimed to evaluate the prognostic impact of surgical resection of recurrent ICC. PATIENTS AND METHODS A total of 345 cases of ICC who underwent hepatectomy with curative intent in 17 institutions were retrospectively analyzed, focusing on recurrence patterns and treatment modalities for recurrent ICC. RESULTS Median survival time and overall 5-year recurrence-free survival rate were 17.8 months and 28.5%, respectively. Recurrences (n = 223) were classified as early (recurrence at ≤1 year, n = 131) or late (recurrence at >1 year, n = 92). Median survival time was poorer for early recurrence (16.3 months) than for late recurrence (47.7 months, p<0.0001). Treatment modalities for recurrence comprised surgical resection (n = 28), non-surgical treatment (n = 134), and best supportive care (BSC) (n = 61). Median and overall 1-/5-year survival rates after recurrence were 39.5 months and 84.6%/36.3% for surgical resection, 14.3 months and 62.5%/2.9% for non-surgical treatment, and 3 months and 4.8%/0% for BSC, respectively (p<0.0001). Multivariate analysis identified early recurrence, simultaneous intra- and extrahepatic recurrence, and surgical resection of recurrence as significant prognostic factors. In subgroup analyses, surgical resection may have positive prognostic impacts on intra- and extrahepatic recurrences, and even on early recurrence. However, simultaneous intra- and extrahepatic recurrence may not see any survival benefit from surgical management. CONCLUSION Surgical resection of recurrent ICC could improve survival after recurrence, especially for patients with intra- or extrahepatic recurrence as resectable oligo-metastases.
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Affiliation(s)
- Toru Kojima
- Department of Surgery, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Yuzo Umeda
- Department of Gastroenterological Surgery, Okayama University, Okayama, Japan
| | - Tomokazu Fuji
- Department of Surgery, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Takefumi Niguma
- Department of Surgery, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Daisuke Sato
- Department of surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Yoshikatsu Endo
- Department of Surgery, Himeji Japanese Red Cross Hospital, Hyogo, Japan
| | - Kenta Sui
- Department of Gastroenterological Surgery at Kochi Health Sciences Center, Kochi, Japan
| | - Masaru Inagaki
- Department of Surgery, National Hospital Organization Fukuyama Medical Center, Hiroshima, Japan
| | - Masahiro Oishi
- Department of Surgery, Tottori Municipal Hospital, Tottori, Japan
| | - Tetsuya Ota
- Department of Surgery, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | | | - Tadakazu Matsuda
- Department of Surgery, Tenwakai Matsuda Hospital, Okayama, Japan
| | - Hideki Aoki
- Department of Surgery, National Hospital Organization Iwakuni Medical Center, Yamaguchi, Japan
| | - Ryuji Hirai
- Department of Surgery, Himeji Saint Mary’s Hospital, Hyogo, Japan
| | - Masashi Kimura
- Department of Surgery, Matsuyama City Hospital, Ehime, Japan
| | - Takahito Yagi
- Department of Gastroenterological Surgery, Okayama University, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University, Okayama, Japan
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Ohira M, Kobayashi T, Hashimoto M, Tazawa H, Abe T, Oshita A, Kohashi T, Irei T, Oishi K, Ohdan H. Prognostic factors in patients with recurrent intrahepatic cholangiocarcinoma after curative resection: A retrospective cohort study. Int J Surg 2018; 54:156-162. [DOI: 10.1016/j.ijsu.2018.04.058] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 04/10/2018] [Accepted: 04/29/2018] [Indexed: 12/19/2022]
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Ying HY, Gong CJ, Feng Y, Jing DD, Lu LG. Serine protease inhibitor Kazal type 1 (SPINK1) downregulates E-cadherin and induces EMT of hepatoma cells to promote hepatocellular carcinoma metastasis via the MEK/ERK signaling pathway. J Dig Dis 2017; 18:349-358. [PMID: 28544403 DOI: 10.1111/1751-2980.12486] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 04/22/2017] [Accepted: 05/17/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate serine protease inhibitor Kazal type 1 (SPINK1) expression and its influence on the prognosis of human hepatocellular carcinoma (HCC) and to explore the underlying molecular mechanisms involved. METHODS Altogether 80 patients with HCC who underwent curative resection were followed up for a median of 58.6 months. SPINK1 expression was detected in the primary HCC samples by immunohistochemistry. Its role in tumor invasion and metastasis was evaluated in vitro by gene silencing using a small interfering RNA-mediated approach, recombinant SPINK1 and U0126 (an inhibitor of MEK/ERK). The proteins in the MEK/ERK signaling pathway were detected by Western blot. RESULTS Patients with high SPINK1 expression showed poor overall survival (P = 0.0001) and recurrence-free survival (P = 0.001) compared with those with low SPINK1 expression. The suppression of SPINK1 resulted in reduced cell migration and invasion. SPINK1 overexpression was significantly associated with increased cell migration and invasion in vitro. Furthermore, SPINK1 promoted cancer cells motility and epithelial-mesenchymal transition (EMT) via the mitogen-activated protein kinase kinase (MAPK) and extracellular regulated kinase (ERK) pathway, resulting in increased vimentin expression and decreased E-cadherin expression. CONCLUSION SPINK1 may be an oncogene that induces EMT via the MEK/ERK pathway and is a potential target for HCC therapy.
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Affiliation(s)
- Hai Yan Ying
- Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Jie Gong
- Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Feng
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Da Dao Jing
- Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Si A, Li J, Xing X, Lei Z, Xia Y, Yan Z, Wang K, Shi L, Shen F. Effectiveness of repeat hepatic resection for patients with recurrent intrahepatic cholangiocarcinoma: Factors associated with long-term outcomes. Surgery 2017; 161:897-908. [DOI: 10.1016/j.surg.2016.10.024] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 09/23/2016] [Accepted: 10/18/2016] [Indexed: 12/19/2022]
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Serine protease inhibitor Kazal type 1 and epidermal growth factor receptor are expressed in pancreatic tubular adenocarcinoma, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 20:620-7. [PMID: 23475261 DOI: 10.1007/s00534-012-0587-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Serine protease inhibitor Kazal type 1 (SPINK1) is expressed in normal human pancreatic acinar cells and in a variety of tumors, and binds to the epidermal growth factor receptor (EGFR), mediating cell proliferation through the mitogen-activated protein kinase cascade in pancreatic cancer cell lines. Here, we aimed to assess SPINK1 and EGFR expression in various neoplastic lesions, including tissues demonstrating precancerous changes. METHODS Surgical specimens of pancreatic ductal adenocarcinoma (n = 23), intraductal papillary mucinous neoplasm (IPMN;n = 21), pancreatic neoplasms other than ductal adenocarcinoma (n = 8), chronic pancreatitis (n = 11), and pancreatic intraepithelial neoplasia (PanIN) lesions within the resected specimens were analyzed immunohistochemically for SPINK1 and EGFR expression. RESULTS Sixty-five PanIN-1A, 32 PanIN-1B, 17 PanIN-2, and 6 PanIN-3 were identified. Both SPINK1 and EGFR were expressed in almost all PanIN lesions. All tubular ductal adenocarcinoma, IPMN, and mucinous cystadenocarcinoma samples (neoplasms of ductal origin) expressed SPINK1, whereas acinar cell carcinoma, anaplastic carcinoma, adenosquamous carcinoma, insulinoma, and islet cell carcinoma did not. EGFR was expressed in 87 % of tubular adenocarcinoma and 48 % of IPMN lesions. Among IPMN lesions, malignant lesions (IPMC) expressed EGFR more often than benign lesions (IPMA) did. Scattered expression of EGFR was observed in normal pancreatic ducts and within the tubular complex within chronic pancreatitis lesions. CONCLUSIONS These results indicate that SPINK1 plays a role as a growth factor, signaling through the EGFR pathway in pancreatic ductal adenocarcinoma and neoplasms, and that the EGFR is involved in the malignant transformation of IPMN.
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Räsänen K, Itkonen O, Koistinen H, Stenman UH. Emerging Roles of SPINK1 in Cancer. Clin Chem 2015; 62:449-57. [PMID: 26656134 DOI: 10.1373/clinchem.2015.241513] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 10/29/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Tumor-associated trypsin inhibitor (TATI) was originally isolated from the urine of a patient with ovarian cancer. It was later shown to be produced by many other tumors and several normal tissues. It had earlier been isolated from the pancreas and was hence called pancreatic secretory trypsin inhibitor (PSTI). It belongs to a family of protease inhibitors presently called serine peptidase inhibitor Kazal type (SPINK). In the SPINK family TATI/PSTI is SPINK1, which is the name used in this review. CONTENT In addition to being a protease inhibitor, SPINK1 also acts as an acute-phase reactant and a growth factor. Furthermore, it has been shown to modulate apoptosis. Overexpression of SPINK1 predicts an unfavorable outcome in several cancers and determination of SPINK1 in serum can be used to identify patients at increased risk of aggressive disease. Thus serum SPINK1 can be used as a prognostic tumor marker. Because SPINK1 acts as a growth factor and an inhibitor of apoptosis in some cancers, it has also been suggested that it can be a therapeutic target in cancer. However, because SPINK1 is the major physiological inhibitor of trypsin, inhibition of SPINK1 may increase the risk of pancreatitis. SUMMARY Taking into account the many functions of SPINK1, assessing the role of SPINK1 in cancer has several potentially important clinical applications ranging from a biomarker to a potential new target for cancer therapy.
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Affiliation(s)
- Kati Räsänen
- Department of Clinical Chemistry, University of Helsinki, Finland
| | - Outi Itkonen
- Department of Clinical Chemistry, University of Helsinki, Finland, Laboratory Division (HUSLAB), Helsinki University Central Hospital, Helsinki, Finland
| | - Hannu Koistinen
- Department of Clinical Chemistry, University of Helsinki, Finland
| | - Ulf-Håkan Stenman
- Department of Clinical Chemistry, University of Helsinki, Finland, Laboratory Division (HUSLAB), Helsinki University Central Hospital, Helsinki, Finland.
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Ida S, Ozaki N, Araki K, Hirashima K, Zaitsu Y, Taki K, Sakamoto Y, Miyamoto Y, Oki E, Morita M, Watanabe M, Maehara Y, Yamamura KI, Baba H, Ohmuraya M. SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer. Mol Cancer Res 2015; 13:1130-8. [PMID: 25804623 DOI: 10.1158/1541-7786.mcr-14-0581] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 03/05/2015] [Indexed: 11/16/2022]
Abstract
UNLABELLED Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. IMPLICATIONS Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.
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Affiliation(s)
- Satoshi Ida
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Nobuyuki Ozaki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
| | - Kotaro Hirashima
- Department of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yoko Zaitsu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsunobu Taki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken-Ichi Yamamura
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaki Ohmuraya
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
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11
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Itkonen O, Stenman UH. TATI as a biomarker. Clin Chim Acta 2014; 431:260-9. [DOI: 10.1016/j.cca.2014.02.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/14/2014] [Accepted: 02/18/2014] [Indexed: 12/22/2022]
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12
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Ling S, Feng T, Jia K, Tian Y, Li Y. Inflammation to cancer: The molecular biology in the pancreas (Review). Oncol Lett 2014; 7:1747-1754. [PMID: 24932227 PMCID: PMC4049733 DOI: 10.3892/ol.2014.2003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 03/11/2014] [Indexed: 02/07/2023] Open
Abstract
Inflammatory responses are known to be correlated with cancer initiation and progression, and exploration of the route from inflammation to cancer makes a great contribution in elucidating the mechanisms underlying cancer development. Pancreatic cancer (PC) is a lethal disease with a low radical-resection rate and a poor prognosis. As chronic pancreatitis is considered to be a significant etiological factor for PC development, the current review aims to describe the molecular pathways from inflammation to pancreatic carcinogenesis, in support of the strategies for the prevention, diagnosis and treatment of PC.
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Affiliation(s)
- Sunbin Ling
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Tingting Feng
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Kaiqi Jia
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yu Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yan Li
- Institute of Cancer Stem Cells, Dalian Medical University, Dalian, Liaoning 116044, P.R. China ; College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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13
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Ruys AT, Groot Koerkamp B, Wiggers JK, Klümpen HJ, ten Kate FJ, van Gulik TM. Prognostic Biomarkers in Patients with Resected Cholangiocarcinoma: A Systematic Review and Meta-analysis. Ann Surg Oncol 2013; 21:487-500. [DOI: 10.1245/s10434-013-3286-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Indexed: 12/11/2022]
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Marshall A, Lukk M, Kutter C, Davies S, Alexander G, Odom DT. Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker. PLoS One 2013; 8:e59459. [PMID: 23527199 PMCID: PMC3601070 DOI: 10.1371/journal.pone.0059459] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 02/18/2013] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. We investigated global gene expression profiles from HCC arising in different liver diseases to test whether HCC development is driven by expression of common or different genes, which could provide new diagnostic markers or therapeutic targets. METHODOLOGY AND PRINCIPAL FINDINGS Global gene expression profiling was performed for 4 normal (control) livers as well as 8 background liver and 7 HCC from 3 patients with hereditary haemochromatosis (HH) undergoing surgery. In order to investigate different disease phenotypes causing HCC, the data were compared with public microarray repositories for gene expression in normal liver, hepatitis C virus (HCV) cirrhosis, HCV-related HCC (HCV-HCC), hepatitis B virus (HBV) cirrhosis and HBV-related HCC (HBV-HCC). Principal component analysis and differential gene expression analysis were carried out using R Bioconductor. Liver disease-specific and shared gene lists were created and genes identified as highly expressed in hereditary haemochromatosis HCC (HH-HCC) were validated using quantitative RT-PCR. Selected genes were investigated further using immunohistochemistry in 86 HCC arising in liver disorders with varied aetiology. Using a 2-fold cut-off, 9 genes were highly expressed in all HCC, 11 in HH-HCC, 270 in HBV-HCC and 9 in HCV-HCC. Six genes identified by microarray as highly expressed in HH-HCC were confirmed by RT qPCR. Serine peptidase inhibitor, Kazal type 1 (SPINK1) mRNA was very highly expressed in HH-HCC (median fold change 2291, p = 0.0072) and was detected by immunohistochemistry in 91% of HH-HCC, 0% of HH-related cirrhotic or dysplastic nodules and 79% of mixed-aetiology HCC. CONCLUSION HCC, arising from diverse backgrounds, uniformly over-express a small set of genes. SPINK1, a secretory trypsin inhibitor, demonstrated potential as a diagnostic HCC marker and should be evaluated in future studies.
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Affiliation(s)
- Aileen Marshall
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom
- Department of Histopathology, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Margus Lukk
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom
| | - Claudia Kutter
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom
| | - Susan Davies
- Department of Histopathology, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Graeme Alexander
- Cambridge Hepatobiliary Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Duncan T. Odom
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom
- Department of Oncology, Addenbrooke's Biomedical Campus, Hutchison-MRC Research Centre, Cambridge, United Kingdom
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Chen YL, Jeng YM, Hsu HC, Lai HS, Lee PH, Lai PL, Yuan RH. Expression of insulin-like growth factor II mRNA-binding protein 3 predicts early recurrence and poor prognosis in intrahepatic cholangiocarcinoma. Int J Surg 2012; 11:85-91. [PMID: 23246869 DOI: 10.1016/j.ijsu.2012.11.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Revised: 11/26/2012] [Accepted: 11/29/2012] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Insulin-like growth factor-II mRNA-binding protein 3 (IMP3), a newly identified oncofetal RNA-binding protein, plays a pivotal role in the regulation of cell growth and migration during early stages of embryogenesis, and is found to be expressed in various human cancers. In this study, we elucidated the clinicopathological significance of IMP3 expression in intrahepatic cholangiocarcinoma (ICC). METHODS From March 1995 to December 2003, 61 surgically resected, unifocal primary ICCs were studied. IMP3 protein expression was detected by immunohistochemical staining. RESULTS IMP3 protein was expressed in 25 of 61 ICCs (41.0%). In addition to correlating with tumor grade (p = 0.0276), tumor stage (p = 0.0059), lymphovascular invasion (p = 0.0198), serum carbohydrate antigen 19-9 level (p = 0.0146), IMP3 expression predicted early tumor recurrence (ETR) (p = 0.0059) and was a strong indicator of worse disease-free survival (p = 0.0001) and overall survival (p = 0.0007). Even though we did not find that IMP3 expression exerted prognostic impact independent of tumor stage, multivariate analysis confirmed that IMP3 expression was an independent risk factor of high-stage tumor and ETR (p = 0.0170, and p = 0.0052, respectively), and thus it contributed to poor prognosis in ICC patients. CONCLUSIONS IMP3 expression can serve as a novel maker for ETR and prognostic prediction, and may be a target for adjuvant therapy of patients with ICC after tumor resection.
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Affiliation(s)
- Yu-Ling Chen
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, and Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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16
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Kume K, Masamune A, Ariga H, Hayashi S, Takikawa T, Miura S, Suzuki N, Kikuta K, Hamada S, Hirota M, Kanno A, Shimosegawa T. Do genetic variants in the SPINK1 gene affect the level of serum PSTI? J Gastroenterol 2012; 47:1267-74. [PMID: 22526274 DOI: 10.1007/s00535-012-0590-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2011] [Accepted: 03/22/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI. METHODS One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit. RESULTS Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 ± 9.6 ng/ml (mean ± SD), and that in healthy controls was 10.7 ± 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1 ± 3.4 ng/ml), but not in those with the p.N34S variant (8.9 ± 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (<6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers. CONCLUSION Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene.
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Affiliation(s)
- Kiyoshi Kume
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan
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17
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Ohmuraya M, Sugano A, Hirota M, Takaoka Y, Yamamura KI. Role of Intrapancreatic SPINK1/Spink3 Expression in the Development of Pancreatitis. Front Physiol 2012; 3:126. [PMID: 22586407 PMCID: PMC3345944 DOI: 10.3389/fphys.2012.00126] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 04/16/2012] [Indexed: 12/17/2022] Open
Abstract
Studies on hereditary pancreatitis have provided evidence in favor of central role for trypsin activity in the disease. Identification of genetic variants of trypsinogen linked the protease to the onset of pancreatitis, and biochemical characterization proposed an enzymatic gain of function as the initiating mechanism. Mutations of serine protease inhibitor Kazal type 1 gene (SPINK1) are shown to be associated with hereditary pancreatitis. We previously reported that Spink3 (a mouse homolog gene of human SPINK1) deficient mice showed excessive autophagy, followed by inappropriate trypsinogen activation in the exocrine pancreas. These data indicate that the role of SPINK1/Spink3 is not only trypsin inhibitor, but also negative regulator of autophagy. On the other hand, recent studies showed that high levels of SPINK1 protein detected in a serum or urine were associated with adverse outcome in various cancer types. It has been suggested that expression of SPINK1 and trypsin is balanced in normal tissue, but this balance could be disrupted during tumor progression. Based on the structural similarity between SPINK1 and epidermal growth factor (EGF), we showed that SPINK1 protein binds and activates EGF receptor, thus acting as a growth factor on tumor cell lines. In this review, we summarize the old and new roles of SPINK1/Spink3 in trypsin inhibition, autophagy, and cancer cell growth. These new functions of SPINK1/Spink3 may be related to the development of chronic pancreatitis.
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Affiliation(s)
- Masaki Ohmuraya
- Institute of Resource Development and Analysis, Kumamoto University Kumamoto, Japan
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18
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Lu F, Lamontagne J, Sun A, Pinkerton M, Block T, Lu X. Role of the inflammatory protein serine protease inhibitor Kazal in preventing cytolytic granule granzyme A-mediated apoptosis. Immunology 2012; 134:398-408. [PMID: 22043941 DOI: 10.1111/j.1365-2567.2011.03498.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Serine protease inhibitor Kazal (SPIK) is an inflammatory protein whose levels are elevated in numerous cancers. However, the role of this protein in cancer development is unknown. We have recently found that SPIK suppresses serine protease-dependent cell apoptosis. Here, we report that anti-SPIK antibodies can co-immmunoprecipitate serine protease granzyme A (GzmA), a cytolytic granule secreted by cytotoxic T lymphocytes and natural killer cells during immune surveillance, and that SPIK suppresses GzmA-induced cell apoptosis. Deletion studies show that the C3-C4 region of SPIK is critical for this suppression. These studies suggest that over-expression of SPIK may prevent GzmA-mediated immune-killing, thereby establishing the tolerance of cancer cells to the body's immune surveillance system. Suppression of over-expressed SPIK can restore the susceptibility of these cells to apoptotic death triggered by GzmA. This finding implies that it is possible to overcome tolerance of cancer cells to the body's immune surveillance system and restore the GzmA-mediated immune-killing by suppressing the over-expression of SPIK.
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Affiliation(s)
- Felix Lu
- Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, College of Medicine, Drexel University, Doylestown, PA 18902, USA
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OHMURAYA M, YAMAMURA KI. The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases. Exp Anim 2011; 60:433-44. [DOI: 10.1538/expanim.60.433] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Masaki OHMURAYA
- Priority Organization for Innovation and Excellence
- Institute of Resource Development and Analysis, Kumamoto University
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20
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Wang GP, Xu CS. Pancreatic secretory trypsin inhibitor: More than a trypsin inhibitor. World J Gastrointest Pathophysiol 2010; 1:85-90. [PMID: 21607145 PMCID: PMC3097947 DOI: 10.4291/wjgp.v1.i2.85] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Revised: 04/15/2010] [Accepted: 04/22/2010] [Indexed: 02/06/2023] Open
Abstract
Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families. Pancreatic secretory trypsin inhibitor (PSTI), also known as serine protease inhibitor Kazal type I(SPINK1), binds rapidly to trypsin, inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen. Therefore, it is an important factor in the onset of pancreatitis. Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis, proliferation and growth of a variety of cell lines. In addition, it takes part in the response to inflammatory factor or injury and is highly related to adult type II citrullinemia.
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21
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Hepatitis B and hepatitis C virus replication upregulates serine protease inhibitor Kazal, resulting in cellular resistance to serine protease-dependent apoptosis. J Virol 2009; 84:907-17. [PMID: 19864383 DOI: 10.1128/jvi.01249-09] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Hepatitis B and C viruses (HBV and HCV, respectively) are different and distinct viruses, but there are striking similarities in their disease potential. Infection by either virus can cause chronic hepatitis, liver cirrhosis, and ultimately, liver cancer, despite the fact that no pathogenetic mechanisms are known which are shared by the two viruses. Our recent studies have suggested that replication of either of these viruses upregulates a cellular protein called serine protease inhibitor Kazal (SPIK). Furthermore, the data have shown that cells containing HBV and HCV are more resistant to serine protease-dependent apoptotic death. Since our previous studies have shown that SPIK is an inhibitor of serine protease-dependent apoptosis, it is hypothesized that the upregulation of SPIK caused by HBV and HCV replication leads to cell resistance to apoptosis. The evasion of apoptotic death by infected cells results in persistent viral replication and constant liver inflammation, which leads to gradual accumulation of genetic changes and eventual development of cancer. These findings suggest a possibility by which HBV and HCV, two very different viruses, can share a common mechanism in provoking liver disease and cancer.
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22
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Ozaki N, Ohmuraya M, Hirota M, Ida S, Wang J, Takamori H, Higashiyama S, Baba H, Yamamura KI. Serine protease inhibitor Kazal type 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor. Mol Cancer Res 2009; 7:1572-81. [PMID: 19737965 DOI: 10.1158/1541-7786.mcr-08-0567] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Serine protease inhibitor, Kazal type 1 (SPINK1) is expressed not only in normal human pancreatic acinar cells but also in a variety of pancreatic ductal neoplasms. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, we hypothesized that SPINK1 binds to EGF receptor (EGFR) to activate its downstream signaling. We first showed that SPINK1 induced proliferation of NIH 3T3 cells and pancreatic cancer cell lines. We showed that SPINK1 coprecipitated with EGFR in an immunoprecipitation experiment and that the binding affinity of SPINK1 to EGFR was about half of that of EGF using quartz-crystal microbalance (QCM) technique. As expected, EGFR and its downstream molecules, signal transducer and activator of transcription 3, v-Akt murine thymoma viral oncogene homologue, and extracellular signal-regulated kinase 1/2, were phosphorylated by SPINK1 as well as EGF. To determine which pathway is the most important for cell growth, we further analyzed the effect of inhibitors. Growth stimulation by EGF or SPINK1 was completely inhibited by EGFR and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor but not by Janus-activated kinase and phosphoinositide 3-kinase inhibitors. To further analyze the clinical importance of SPINK1 in the development of pancreatic cancer, we examined the expression of SPINK1 and EGFR in pancreatic tubular adenocarcinomas and pancreatic intraepithelial neoplasm. Both SPNK1 and EGFR were coexpressed not only in the early stage of cancer, PanIN-1A, but also in advanced stages. Taken together, these results suggest that SPINK1 stimulates the proliferation of pancreatic cancer cells through the EGFR/mitogen-activated protein kinase cascade.
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Affiliation(s)
- Nobuyuki Ozaki
- Division of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
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23
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Kikuchi I, Uchinami H, Nanjo H, Hashimoto M, Nakajima A, Kume M, Mencin A, Yamamoto Y. Clinical and prognostic significance of urinary trypsin inhibitor in patients with hepatocellular carcinoma after hepatectomy. Ann Surg Oncol 2009; 16:2805-17. [PMID: 19636634 DOI: 10.1245/s10434-009-0622-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 06/18/2009] [Accepted: 06/18/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Urinary trypsin inhibitor (UTI), produced in the liver, has been considered to suppress inflammation. The production of UTI may decrease after a hepatectomy and thereby increase the incidence of postoperative inflammation. This study investigated whether the changes in the UTI level affected the postoperative course in patients undergoing a hepatectomy for hepatocellular carcinoma (HCC). The prognostic significance of UTI was also analyzed. METHODS The perioperative plasma UTI was measured in 25 HCC patients who underwent hepatic resection, and the correlation between the kinetics of UTI and clinicopathological factors was investigated. The expression of UTI in the resected specimens was examined by immunohistochemistry in 65 patients. Expression of UTI in the cancer cells were then correlated to both the liver pathology and the clinical outcomes in the corresponding patients. RESULTS The plasma UTI level greatly decreased on the first postoperative day. This decrease significantly correlated with the resected tumor volume (r (s) = -.530, P = .006), but it had no influence on inflammatory complications. Immunohistochemistry revealed UTI expression in both noncancerous and cancerous lesions. An overexpression of UTI in HCC tissue was found to be an independent prognostic factor for early recurrence (P = .006). CONCLUSIONS Although UTI plasma levels were noted to decrease after the removal of an HCC tumor, this decrease did not lead to an increase in inflammatory complications. However, overexpression of UTI in cancer was found to be a risk factor for tumor recurrence after resection, suggesting that UTI expression may be a useful prognostic marker.
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Affiliation(s)
- Isao Kikuchi
- Department of Gastroenterological Surgery, Akita University School of Medicine, Akita, Japan
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24
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Jhavar S, Brewer D, Edwards S, Kote-Jarai Z, Attard G, Clark J, Flohr P, Christmas T, Thompson A, Parker M, Shepherd C, Stenman UH, Marchbank T, Playford RJ, Woodhouse C, Ogden C, Fisher C, Kovacs G, Corbishley C, Jameson C, Norman A, De-Bono J, Bjartell A, Eeles R, Cooper CS. Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer. BJU Int 2009; 103:1256-69. [PMID: 19040532 DOI: 10.1111/j.1464-410x.2008.08200.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates. MATERIALS AND METHODS We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS The expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to beta-oestradiol, and to retinoic acid. CONCLUSIONS Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome.
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Affiliation(s)
- Sameer Jhavar
- Institute of Cancer Research, Male Urological Cancer Research Centre, Sutton, Surrey, UK
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25
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Briggs CD, Neal CP, Mann CD, Steward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer 2009; 45:33-47. [PMID: 18938071 DOI: 10.1016/j.ejca.2008.08.024] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2008] [Revised: 08/06/2008] [Accepted: 08/26/2008] [Indexed: 12/24/2022]
Abstract
The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.
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Affiliation(s)
- Christopher D Briggs
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, Leicester, United Kingdom.
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26
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Lu X, Lamontagne J, Lu F, Block TM. Tumor-associated protein SPIK/TATI suppresses serine protease dependent cell apoptosis. Apoptosis 2008; 13:483-94. [PMID: 18347987 DOI: 10.1007/s10495-008-0193-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Serine protease dependent cell apoptosis (SPDCA) is a recently described caspase independent innate apoptotic pathway. It differs from the traditional caspase dependent apoptotic pathway in that serine proteases, not caspases, are critical to the apoptotic process. The mechanism of SPDCA is still unclear and further investigation is needed to determine any role it may play in maintaining cellular homeostasis and development of disease. The current knowledge about this pathway is limited only to the inhibitory effects of some serine protease inhibitors. Synthetic agents such as pefabloc, AEBSF and TPCK can inhibit this apoptotic process in cultured cells. There is little known, however, about biologically active agents available in the cell which can inhibit SPDCA. Here, we show that over-expression of a cellular protein called serine protease inhibitor Kazal (SPIK/TATI/PSTI) results in a significant decrease in cell susceptibility to SPDCA, suggesting that SPIK is an apoptosis inhibitor suppressing this pathway of apoptosis. Previous work has associated SPIK and cancer development, indicating that this finding will help to open the doorway for further study on the mechanism of SPDCA and the role it may play in cancer development.
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Affiliation(s)
- Xuanyong Lu
- Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, College of Medicine, Drexel University, 3805 Old Easton Road, Doylestown, PA 18902, USA.
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27
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Bonney GK, Craven RA, Prasad R, Melcher AF, Selby PJ, Banks RE. Circulating markers of biliary malignancy: opportunities in proteomics? Lancet Oncol 2008; 9:149-58. [PMID: 18237849 DOI: 10.1016/s1470-2045(08)70027-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholangiocarcinoma, a primary liver tumour that arises from biliary epithelial cells, is increasing in incidence and has poor prognosis. Diagnosis is difficult, particularly in patients with primary sclerosing cholangitis, who are at risk of developing the disease. Timely diagnosis is essential because surgical resection in early disease remains the only cure. The lack of a sensitive and specific early diagnostic marker and of alternative treatments are the main reasons why patients have limited survival. The use of proteomic-based approaches, which analyse the physiological or pathological complement of proteins (ie, the proteome) in cells, tissues, or biological fluids, has received substantial interest in biomarker discovery. Proteomics complements genomic studies and examines functional end-units quantitatively and qualitatively, including post-translational modifications which might vary with disease and might have key roles in protein function or localisation. Major advances in technology and bioinformatics have enhanced proteomic studies, resulting in increased understanding of the pathogenesis of many diseases and in biomarker discovery with effective use of tissues, cell lines, and biological fluids. We review the current status and promise of proteomic-based approaches in biomarker discovery for cholangiocarcinoma.
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Affiliation(s)
- Glenn K Bonney
- Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, UK
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Lempinen M, Isoniemi H, Mäkisalo H, Nordin A, Halme L, Arola J, Höckerstedt K, Stenman UH. Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol 2007; 47:677-83. [PMID: 17640760 DOI: 10.1016/j.jhep.2007.05.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2007] [Revised: 05/24/2007] [Accepted: 05/31/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma. Our aim was to evaluate the diagnostic value of trypsinogen-1, trypsinogen-2, tumour-associated trypsin inhibitor, human chorionic gonadotropin beta and trypsin-2-alpha(1)-antitrypsin for cholangiocarcinoma and to compare them with CA19-9 and CEA. METHODS The study consisted of 84 patients with either PSC or cholangiocarcinoma or both referred for liver transplantation or other liver surgery. The serum concentrations were determined by time-resolved immunofluorometric assays. RESULTS Forty-six patients were transplanted due to PSC; in 3 of the explanted livers cholangiocarcinoma was found incidentally. All transplanted patients had severe biliary strictures together with cirrhosis or pre-cirrhosis. Twenty-nine of 38 patients with cholangiocarcinoma were candidates for intervention. In all, 8 patients had both PSC and cholangiocarcinoma. Receiver-operating characteristics curve analysis showed that serum trypsinogen-2 had the highest accuracy in differentiating between cholangiocarcinoma and PSC. The area under the curve (AUC) value was 0.804 for trypsinogen-2 and 0.613 for CA19-9. Serum trypsinogen-2 also showed the highest accuracy for differentiation between PSC and PSC with simultaneous cholangiocarcinoma with an AUC value of 0.759. CONCLUSIONS Our results suggest that serum trypsinogen-2 is a most useful marker for diagnosing patients with cholangiocarcinoma, and it is superior to serum CA19-9 and CEA.
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Affiliation(s)
- Marko Lempinen
- Clinic of Surgery, Department of Transplantation and Liver Surgery, Helsinki University Hospital, P.O. Box 263, FIN 00029, Helsinki, Finland.
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