Emerging Roles of SPINK1 in Cancer

Räsänen, Kati; Itkonen, Outi; Koistinen, Hannu; Stenman, Ulf‐Håkan

doi:10.1373/clinchem.2015.241513

Cited by 65 publications

(75 citation statements)

References 77 publications

(97 reference statements)

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“…Like IL‐6, SPINK1 has been shown to affect cancer cell growth and motility . Recently, Mehner and coworkers showed that recombinant SPINK1 at concentrations of 10 and 100 nM increased proliferation of ovarian cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Both IL‐6 and SPINK1 are known to regulate many cellular functions, such as growth, differentiation, and motility . Contradicting results of IL‐6 in colon cancer growth have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, new molecular targets for treatment of metastasized CRC are needed. SPINK1 tissue expression has been found in around 55% of CRC tumors and significantly higher levels were observed in advanced cancer stages . Furthermore, elevated SPINK1 serum levels have been observed in 50% of colon cancer patients and it was shown to be a useful marker for distinguishing patients with liver metastasis .…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma

Räsänen

Lehtinen

Nokelainen

et al. 2015

Molecular Carcinogenesis

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Inflammation promotes colorectal cancer (CRC) tumorigenesis, but the underlying molecular mechanisms are still being uncovered. Proinflammatory cytokine interleukin-6 (IL-6) stimulates survival signaling in CRC; inflammatory signals also regulate production and activity of proteases and their inhibitors. Over-expression of serine protease inhibitor Kazal type 1 (SPINK1) predicts an unfavorable outcome in colon cancer. The SPINK1 gene contains an IL-6 responsive element, suggesting it could act as an acute phase reactant. We assessed the connection between IL-6 and SPINK1, and the function and mechanism of this signaling. Our results show that Colo205 and HT-29 cells express and secrete SPINK1, and both fibroblast-derived and recombinant IL-6 further increased the SPINK1 levels. Concurrently CRC cells augmented the IL-6 production in fibroblasts. In CRC tissues cancer cells were positive for SPINK1, whereas IL-6 was found in stromal cells. In Colo205 cells IL-6 also stimulated the secretion of trypsin-1 and -2, the key targets of SPINK1 protease inhibition, whereas in HT-29 cells trypsin-1 and -2 levels remained constantly low. Functionally, both IL-6 and SPINK1 increased the motility of the CRC cells. Mechanistically, IL-6 activated the canonical STAT3 pathway and inhibition of STAT3 phosphorylation decreased the levels of SPINK1, trypsin-1 and -2. Taken together, our results indicate a novel link between inflammatory signals originating from the tumor microenvironment and increased SPINK1 levels. This finding has potential therapeutic implications for targeted therapy, as it confirms that SPINK1 acts as an acute phase reactant and that it participates in the paracrine crosstalk with the tumor microenvironment of colon cancer. © 2015 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interleukin‐6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma

Räsänen

Lehtinen

Nokelainen

et al. 2015

Molecular Carcinogenesis

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“…1G) levels. Since, SPINK1 overexpression has also been implicated in colorectal, lung, pancreatic, and ovarian cancers (20), we sought to examine if SPINK1 is regulated by a similar mechanism in cancers of different cellular/tissue origins. Thus, we determined the status of SPINK1 expression in multiple cancer cell lines (Supplementary Fig.…”

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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“…Subsequently, SPINK1 was found to be abnormally expressed in solid tumors, including PCa 4. As a result of this, further studies were devoted to investigating whether this peptide was associated with the prognosis of PCa.…”

Section: Introductionmentioning

confidence: 99%

The association between SPINK1 and clinical outcomes in patients with prostate cancer: a systematic review and meta-analysis

Zhang¹,

Yin

Shen³

et al. 2017

OTT

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Evidence of the prognostic role of serine peptidase inhibitor Kazal type 1 (SPINK1) in prostate cancer (PCa) is controversial. The aim of this study was, therefore, to evaluate the association between SPINK1 and clinical outcomes in PCa. Searches were made of PubMed, Medline, Embase, and the China Biology Medicine disc (CBMdisc) up to January 2017. The Newcastle–Ottawa Scale was used to assess the risk of bias of included studies. RevMan software was used to perform meta-analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was employed for assessing the quality of the evidence. Ten studies with 17,161 patients were included in the analysis. Random-effect models were adopted for all outcomes with significant heterogeneities. In patients treated with radical prostatectomy, SPINK1 was associated with biochemical recurrence (BCR) (hazard ratio [HR] =1.41, 95% confidence interval [CI]: 1.01–1.97; P=0.04), but not PCa-specific mortality (HR =0.93, 95% CI: 0.33–2.57; P=0.88), and overall survival (OS) (HR =0.89, 95% CI: 0.58–1.35; P=0.57). In metastatic PCa, SPINK1 was significantly associated with castration-resistant PCa-free survival (HR =3.87, 95% CI: 1.87–8.00; P=0.0003) and OS (HR =2.59, 95% CI: 1.16–5.78; P=0.02). However, the quality of the evidence was very low for all study outcome measures. In conclusion, although SPINK1 was not a predictor of PCa mortality or OS among patients who underwent radical prostatectomy, it may have prognostic value in metastatic PCa.

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Emerging Roles of SPINK1 in Cancer

Cited by 65 publications

References 77 publications

Interleukin‐6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma

Interleukin‐6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma

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

The association between SPINK1 and clinical outcomes in patients with prostate cancer: a systematic review and meta-analysis

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