Specific expression of the pancreatic‐secretory‐trypsin‐inhibitor (PSTI) gene in hepatocellular carcinoma

Ohmachi, Yoshitaka; Murata, Atsuo; Yasuda, Tadashi; Yasuda, Takushi; Monden, Morito; Mori, Takesada; Ogawa, Michio; Matsubara, Kazuo

doi:10.1002/ijc.2910550505

Cited by 51 publications

(45 citation statements)

References 23 publications

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“…Furthermore, these results suggest that SPINK1 overexpression could be used as a diagnostic marker for HCC. The plasma concentrations of SPINK1 are significantly increased in HCC patients and the concentrations correlated with tumor size (37 ). Recently, serum SPINK1 has been found to be a strong prognostic factor in HCC (41 ).…”

Section: Hepatocellular Cancermentioning

confidence: 99%

Emerging Roles of SPINK1 in Cancer

et al. 2016

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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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Section: Hepatocellular Cancermentioning

confidence: 99%

Emerging Roles of SPINK1 in Cancer

et al. 2016

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“…SPINK1 is also produced in cancers of the colon (15,16), lung (17,18), liver (19), breast (20), prostate (21), and pancreas (20,22). In colon cancer, Gouyer and colleagues (23) identified and characterized SPINK1 as a major proinvasive secreted factor from the conditioned medium of HT-29 5M21 human colon cancer cells, which express a spontaneous invasive phenotype.…”

Section: Introductionmentioning

confidence: 99%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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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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“…Its role has been considered to be a specific inhibitor that prevents autoactivation of trypsinogen in the pancreas and pancreatic juice [41]. Later studies showed that PSTI was also expressed in some extrapancreatic normal tissues [39,4345] and in various cancers, including pancreatic [34], colorectal [35], gastric [36], lung [37], and hepatocellular [38] cancers. It was found that the serum concentration of immunoreactive PSTI is elevated after surgery, trauma and severe infection [45][46][47], suggesting that PSTI is an acute phase reactant.…”

Section: Controlmentioning

confidence: 99%

“…2 and 3), although the liver specimens of most type I1 patients tested in the present paper did not show any histological appearance as cancer. It was suggested that the PSTI gene is regulated by the AP-I binding site and IL-6 responsive element, and each region is active in hepatoma cells [38]. However, the biological implication of the high PSTI gene expression in hepatic cancer is not yet understood.…”

Section: Controlmentioning

confidence: 99%

Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

et al. 1995

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Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS is deficient specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there are no apparent abnormalities in the amount, translational activity, and nucleotide sequence of hepatic ASS mRNA. Recent results of homozygosity testing indicate that the primary defect of type II citrullinemia is not within the ASS gene locus. In this present work, to understand the pathogenesis and pathophysiology of type II citrullinemia, we have characterized the alterations of gene expression in the liver of type II patients using the recently developed mRNA differential display method. Some cDNA bands expressed differently in type 1I citrullinemia patients and control were selected, cloned, and sequenced. Nucleotide sequence analysis and homology searching revealed an interesting clone which has 99% homology with the human pancreatic secretory trypsin inhibitor (hPSTI). Northern blot and RT-PCR analyses showed that the expression of hPSTI mRNA increased significantly in the liver of all type II patients tested. Furthermore, the concentration of hPSTI protein was found to be higher in the liver of type II citrullinemia than in control. These results suggest that hPST! may be related to the primary defect of type II citrullinemia and may be useful as a diagnostic marker, although the detailed mechanism of the high expression of hPSTI mRNA in type 11 liver is not yet known.

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Specific expression of the pancreatic‐secretory‐trypsin‐inhibitor (PSTI) gene in hepatocellular carcinoma

Cited by 51 publications

References 23 publications

Emerging Roles of SPINK1 in Cancer

Emerging Roles of SPINK1 in Cancer

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult‐onset type II citrullinemia

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