The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

Tomlins, Scott A.; Rhodes, Daniel R.; Yu, Jianjun; Varambally, Sooryanarayana; Mehra, Rohit; Perner, Sven; Demichelis, Francesca; Helgeson, Beth E.; Laxman, Bharathi; Morris, David S.; Cao, Qi; Cao, Xuhong; Andrén, Ove; Fall, Katja; Johnson, Laura A.; Wei, John T.; Shah, Rajal B.; Al‐Ahmadie, Hikmat; Eastham, James A.; Eggener, Scott E.; Fine, Samson W.; Hotakainen, Kristina; Stenman, Ulf Håkan; Tsodikov, Alex; Gerald, William L.; Lilja, Hans; Reuter, Victor E.; Kantoff, Philip W.; Scardino, Peter T.; Rubin, Mark A.; Bjartell, Anders; Chinnaiyan, Arul M.

doi:10.1016/j.ccr.2008.04.016

Cited by 297 publications

(346 citation statements)

References 46 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: 84%

“…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: 84%

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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“…While TMPRSS2-ERG fusion forms the most frequent molecular subtype, a significant subset of ETS-negative (-) PCa show overexpression of Serine Peptidase Inhibitor, Kazal type-1 (SPINK1) in ~10-15% of the total PCa patients, a distinct subtype defined by overall higher Gleason score, shorter progression-free survival and biochemical recurrence (10,11). SPINK1 promotes cell proliferation and invasion through autocrine/paracrine signaling and mediate its oncogenic effects in part through EGFR interaction by activating downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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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The Role of SPINK1 in ETS Rearrangement-Negative Prostate Cancers

Cited by 297 publications

References 46 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

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

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

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