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

Ozaki, Noriatsu; Ohmuraya, Masaki; Hirota, Masahiko; Ida, Satoshi; Wang, Jun; Takahashi, Hiroshi; Higashiyama, Shigeki; Baba, Hideo; Yamamura, Ken Ichi

doi:10.1158/1541-7786.mcr-08-0567

Cited by 97 publications

(100 citation statements)

References 47 publications

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“…There is a 50% gene sequence homology between SPINK1 and EGF (37)(38)(39). Recently, we showed that SPINK1 binds to EGF receptor (EGFR) to activate its downstream signaling, resulting in the proliferation of pancreatic and breast cancer cells (22). In the current study, we showed that tumor number and volume were significantly decreased in Spink3 lacZ/þ compared with wild-type mice.…”

Section: Discussionmentioning

confidence: 55%

“…All resections for colorectal cancer were performed between 1994 and 2007 at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan. Immunohistochemical staining was performed according to a previously described protocol (22). Each sample was excised and fixed in 10% buffered formalin for histologic examination.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…It was fixed by 10% buffered formalin for 24 hours, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E). Colitis was evaluated on H&E-stained sections, according to the morphologic criteria described by Cooper and colleagues (30) Western blot analysis Conventional Western blot analysis was performed as previously described (22). Rabbit anti-mouse Spink3 antibody (Cell Signaling Technology) and rabbit anti-mouse actin antibody (Sigma-Aldrich) were used at 1:1,000 and 1:2,000, respectively.…”

Section: Histologic Analysismentioning

confidence: 99%

“…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%

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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: 55%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Histologic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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 the clinical practice, the MUC1 cytoplasmic staining is used as an indicator of malignancy on cytology obtained by fine-needle aspiration of the pancreas (Wang et al, 2007). Interestingly, EGFR is also aberrantly expressed in pancreatic cancer from intraepithelial neoplasia lesions to PDAC and exhibits membrane and cytoplasmic staining (Ozaki et al, 2009). Previous reports demonstrated that MUC1 physically interacts with EGFR at the cell membrane, promotes its endocytosis and recycling, and inhibits its degradation (Li et al, 2001;Schroeder et al, 2001;Pochampalli et al, 2007;Ramasamy et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

et al. 2011

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MUC1 is a transmembrane glycoprotein which is typically expressed at the apical membrane of normal epithelial cells. In cancer cells, the over-expression of MUC1 and its aberrant localization around the cell membrane and in the cytoplasm favours its interaction with different protein partners such as epidermal growth factor receptor (EGFR) and can promote tumour proliferation through the activation of oncogenic signalling pathways. Our aims were to study the mechanisms inducing MUC1 cytoplasmic localization in pancreatic cancer cells, and to decipher their impact on EGFR cellular localization and activation. Our results showed that galectin-3, an endogenous lectin, is coexpressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus. On the contrary, silencing of galectin-3 led to a decrease of cyclin-D1 levels and of cell proliferation. The galectin-3-dependent regulation of MUC1/EGFR functions may represent an interesting mechanism modulating the EGFR-stimulated cell growth of pancreatic cancer cells.

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Serine peptidase inhibitor Kazal type I (SPINK1) promotes BRL‐3A cell proliferation via p38, ERK, and JNK pathways

Chang

Zhao

Luo

et al. 2017

Cell Biochemistry & Function

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Serine peptidase inhibitor Kazal type I (SPINK1) has the similar spatial structure as epidermal growth factor (EGF); EGF can interact with epidermal growth factor receptor (EGFR) to promote proliferation in different cell types. However, whether SPINK1 can interact with EGFR and further regulate the proliferation of hepatocytes in liver regeneration remains largely unknown. In this study, we investigated the role of SPINK1 in a rat liver hepatocyte line of BRL-3A in vitro. The results showed the upregulation of endogenous Spink1 (gene addition) significantly increased not only the cell viability, cell numbers in S and G /M phase, but also upregulated the genes/proteins expression related to cell proliferation and anti-apoptosis in BRL-3A. In contrast, the cell number in G phase and the expression of pro-apoptosis-related genes/proteins were significantly decreased. The similar results were observed when the cells were treated with exogenous rat recombinant SPINK1. Immunoblotting suggested SPINK1 can interact with EGFR. By Ingenuity Pathway Analysis software, the SPINK1 signalling pathway was built; the predicted read outs were validated by qRT-PCR and western blot; and the results showed that p38, ERK, and JNK pathways-related genes/proteins were involved in the cell proliferation upon the treatment of endogenous Spink1 and exogenous SPINK1. Collectively, SPINK1 can associate with EGFR to promote the expression of cell proliferation-related and anti-apoptosis-related genes/proteins; inhibit the expression of pro-apoptosis-related genes/proteins via p38, ERK, and JNK pathways; and consequently promote the proliferation of BRL-3A cells. For the first time, we demonstrated that SPINK1 can associate with EGFR to promote the proliferation of BRL-3A cells via p38, ERK, and JNK pathways. This work has direct implications on the underlying mechanism of SPINK1 in regulating hepatocytes proliferation in vivo and liver regeneration after partial hepatectomy.

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

Cited by 97 publications

References 47 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

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

Serine peptidase inhibitor Kazal type I (SPINK1) promotes BRL‐3A cell proliferation via p38, ERK, and JNK pathways

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