Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma

Lee, Y.-C.; Pan, Hung‐Wei; Shu, Peng; Lai, Po-Lin; Kuo, Wen-Ling; Ou, Yueh‐Hsing; Hsu, Hey‐Chi

doi:10.1016/j.ejca.2006.11.020

Cited by 54 publications

(52 citation statements)

References 22 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 patients with stage III and IV ovarian cancers, TATI tissue expression and elevated TATI concentration in serum were associated with adverse cancer-specific and progression-free survival (Paju et al, 2004). Of note, TATI overexpression correlates with anchorage-independent growth, high stage HCC, portal vein invasion, early tumor recurrence and metastasis (Lee et al, 2007). Our future efforts will be aimed at exploring sporadic and familial human colon tumors, as well as mucinous and nonmucinous neoplasms, for their ability to produce high levels of TATI.…”

Section: Discussionmentioning

confidence: 99%

“…Increased levels of trypsinogen, tumor-associated trypsinogens, trypsin and its inhibitor TATI correlate with the malignancy of human solid tumors (Nyberg et al, 2006). The presence of TATI in tumors is a marker of adverse prognosis for hepatocellular carcinoma (HCC), bladder, kidney and mucinous ovarian cancers (Stenman, 2002;Antila et al, 2006;Lee et al, 2007;Paju et al, 2007). In patients with stage III and IV ovarian cancers, TATI tissue expression and elevated TATI concentration in serum were associated with adverse cancer-specific and progression-free survival (Paju et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

et al. 2008

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From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasisrelated genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6-and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

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“…SPINK1 mRNA is expressed in hepatocellular carcinoma (HCC) associated with hepatitis (37 ) and overexpression of SPINK1 is associated with adverse prognosis (38 ). Global gene expression profiling and immunohistochemistry have shown that SPINK1 is the most strongly upregulated gene in hereditary hemochromatosis-related HCC (39 ).…”

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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Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma

Cited by 54 publications

References 22 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

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells

Emerging Roles of SPINK1 in Cancer

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