Relationship Between Pancreatic Secretory Trypsin Inhibitor and Early Recurrence of Intrahepatic Cholangiocarcinoma Following Surgical Resection

Tonouchi, Akihiko; Ohtsuka, Masayuki; Ito, Hiroshi; Kimura, Fumio; Shimizu, Hiroaki; Kato, Masaki; Nimura, Yuji; Iwase, Katsuro; Hiwasa, Takaki; Seki, Naohiko; Takao, Masaki; Miyazaki, Masaru

doi:10.1111/j.1572-0241.2006.00612.x

Cited by 31 publications

(30 citation statements)

References 31 publications

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“…Increased expression of SPINK1 in tumor tissue has been reported in patients with poor survival (21,25,(45)(46)(47)(48) and favorable prognosis (9,24,43). As shown above, SPINK1/ Spink3 acts as a growth factor in colorectal cancer.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…In intrahepatic cholangiocarcinoma, overexpression of SPINK1 has been detected by DNA microarray analysis. High expression of SPINK1 in tumor tissue is associated with recurrence of intrahepatic cholangiocarcinoma (74 ).…”

Section: Other Cancersmentioning

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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“…Thus far, the expression of SPINK1 in tumor cells has been explained by its coexpression with tumor-associated trypsin, which is thought to participate in tumor-associated protease cascades mediating tumor invasion (13). However, the role of SPINK1 in malignant tumors remains to be elucidated (19).…”

Section: Introductionmentioning

confidence: 99%

“…SPINK1 is also a marker of poor prognosis (3,(17)(18)(19)(20). Quantitative RT-PCR identified SPINK1 as a gene associated with early recurrence of intrahepatic cholangiocarcinoma after resection (19). Thus far, the expression of SPINK1 in tumor cells has been explained by its coexpression with tumor-associated trypsin, which is thought to participate in tumor-associated protease cascades mediating tumor invasion (13).…”

Section: Introductionmentioning

confidence: 99%

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Serine Protease Inhibitor Kazal Type 1 Promotes Proliferation of Pancreatic Cancer Cells through the Epidermal Growth Factor Receptor

Ozaki

Ohmuraya

Hirota

et al. 2009

Molecular Cancer Research

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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. (Mol Cancer Res 2009;7(9):1572-81)

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Relationship Between Pancreatic Secretory Trypsin Inhibitor and Early Recurrence of Intrahepatic Cholangiocarcinoma Following Surgical Resection

Abstract: PSTI might be a potential marker for identifying ICC patients with an increased risk of early recurrence after surgical resection.

Cited by 31 publications

References 31 publications

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

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

Emerging Roles of SPINK1 in Cancer

Serine Protease Inhibitor Kazal Type 1 Promotes Proliferation of Pancreatic Cancer Cells through the Epidermal Growth Factor Receptor

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