Gene Summary

Gene:SPINK1; serine peptidase inhibitor, Kazal type 1
Aliases: TCP, PCTT, PSTI, TATI, Spink3
Summary:The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serine protease inhibitor Kazal-type 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Signal Transduction
  • Pancreatitis
  • DNA-Binding Proteins
  • Disease Progression
  • Lung Cancer
  • Biomarkers, Tumor
  • SPINK1
  • Oligonucleotide Array Sequence Analysis
  • Cancer Gene Expression Regulation
  • Chromosome 5
  • Adenocarcinoma
  • Risk Factors
  • Hepatocellular Carcinoma
  • Immunohistochemistry
  • Proto-Oncogene Proteins c-ets
  • Mutation
  • Tumor Suppressor Proteins
  • Trypsinogen
  • Gene Expression Profiling
  • Genetic Testing
  • p53 Protein
  • FISH
  • Cohort Studies
  • Carrier Proteins
  • Messenger RNA
  • Prostate Cancer
  • Sensitivity and Specificity
  • Pancreatitis, Chronic
  • Transcriptional Regulator ERG
  • Pancreatic Cancer
  • Bladder Cancer
  • Oncogene Fusion Proteins
  • Transfection
  • Trypsin Inhibitor, Kazal Pancreatic
  • PTEN
  • Trypsin
  • Genetic Predisposition
  • Urothelium
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Trans-Activators
  • Liver Cancer
  • Spliceosomes
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SPINK1 (cancer-related)

Iida-Norita R, Kawamura M, Suzuki Y, et al.
Vasohibin-2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma.
Cancer Sci. 2019; 110(7):2296-2308 [PubMed] Free Access to Full Article Related Publications
Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-Kras

Bhatia V, Yadav A, Tiwari R, et al.
Epigenetic Silencing of miRNA-338-5p and miRNA-421 Drives SPINK1-Positive Prostate Cancer.
Clin Cancer Res. 2019; 25(9):2755-2768 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
PURPOSE: Serine peptidase inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in prostate cancer remains largely unknown.
EXPERIMENTAL DESIGN: miRNA prediction tools were employed to examine the
RESULTS: We established a critical role of miRNA-338-5p/-421 in posttranscriptional regulation of
CONCLUSIONS: Our findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive prostate cancer, although restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.

Hasan A, Moscoso DI, Kastrinos F
The Role of Genetics in Pancreatitis.
Gastrointest Endosc Clin N Am. 2018; 28(4):587-603 [PubMed] Related Publications
Individuals with acute recurrent and chronic pancreatitis may have an inherited predisposition to the development of the disease. Pancreatitis in the setting of a significant family history of the disease can be classified as hereditary or familial pancreatitis. In this article, the authors closely examine the specific genes implicated in pancreatitis, investigate the role of genetic testing for diagnosis, and describe the impact of genetic testing results on clinical management.

Cazacu IM, Farkas N, Garami A, et al.
Pancreatitis-Associated Genes and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis.
Pancreas. 2018; 47(9):1078-1086 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
OBJECTIVE: The aim of this study was to evaluate the connection between pancreatic cancer (PC) and genetic variants associated with chronic pancreatitis via systematic review and meta-analysis.
METHODS: The data search was performed in 3 major databases (PubMed, Embase, and Cochrane Library). The selected studies have looked into the presence of the pancreatitis-associated genes in patients with PC and in control subjects, the outcome being the frequency of the mutations in the 2 groups. For the binary outcomes, pooled odds ratio (OR) and 95% confidence interval (CI) were calculated.
RESULTS: Ten articles proved to be eligible for the qualitative synthesis, and 8 articles were suitable for statistical analysis. Six case-control studies, comprising 929 PC cases and 1890 control subjects for serine protease inhibitor Kazal type 1 (SPINK1) mutations, and 5 case-control studies, comprising 1674 PC cases and 19,036 control subjects for CFTR mutations, were enrolled in our analysis. SPINK1 mutations showed no association with PC (OR, 1.52; 95% CI, 0.67-3.45; P = 0.315), whereas mutations in CFTR modestly increased the risk of PC (OR, 1.41; 95% CI, 1.07-1.84; P = 0.013).
CONCLUSION: Our meta-analysis showed that mutations in CFTR modestly increase the risk of PC, whereas no association was found between SPINK1 and PC.

Zhan W, Shelton CA, Greer PJ, et al.
Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.
Pancreas. 2018; 47(8):924-936 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

Koide H, Kimura T, Inaba H, et al.
Comparison of ERG and SPINK1 expression among incidental and metastatic prostate cancer in Japanese men.
Prostate. 2019; 79(1):3-8 [PubMed] Related Publications
BACKGROUND: TMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal-type 1 (SPINK1) was almost exclusively defined in ERG-negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts.
METHODS: A total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients.
RESULTS: The overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre-treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration-resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71).
CONCLUSIONS: ERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration-sensitive PCa.

Tamura K, Yu J, Hata T, et al.
Mutations in the pancreatic secretory enzymes
Proc Natl Acad Sci U S A. 2018; 115(18):4767-4772 [PubMed] Free Access to Full Article Related Publications
To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

Yang X, Ren H, Shao Y, et al.
Chaperonin-containing T‑complex protein 1 subunit 8 promotes cell migration and invasion in human esophageal squamous cell carcinoma by regulating α-actin and β-tubulin expression.
Int J Oncol. 2018; 52(6):2021-2030 [PubMed] Related Publications
The chaperonin-containing T‑complex protein 1 (CCT) has eight subunits, CCT 1-8, which are dysregulated in several types of cancer. To determine how subunit 8 (CCT8) influences the development of esophageal squamous cell carcinoma (ESCC), immunohistochemistry and western blot analysis were performed on 128 ESCC samples in the present study to measure the expression of CCT8. The prognostic value of CCT8 was analyzed using univariate and multivariate survival analyses. CCT8 knockdown in ESCC cells was performed and subsequently, the migration and invasion of ESCC cells was assessed. The results of immunohistochemistry and western blot analysis of ESCC tissue indicated that the expression of CCT8 in tumor tissues from patients with lymph node metastasis (LNM) was high whereas its expression in tissues from those without LNM was low. In addition, the overall survival rate of patients with high CCT8 expression was poor. It was demonstrated that CCT8 influenced the migration and invasion of ESCC cells by regulating α-actin and β-tubulin. Following CCT8 knockdown, cells were treated with cisplatin; it was demonstrated that α-actin and β-tubulin were downregulated and that cell apoptosis was enhanced. These data confirm that α-actin and β-tubulin are regulated by CCT8, and that increased CCT8 expression is associated with poor patient prognosis and cisplatin resistance in ESCC.

Visseaux L, Durlach A, Barete S, et al.
T-cell papulosis associated with B-cell malignancy: a distinctive clinicopathologic entity.
J Eur Acad Dermatol Venereol. 2018; 32(9):1469-1475 [PubMed] Related Publications
BACKGROUND: A distinctive eruption referred to as 'insect bite-like reaction' or 'eosinophilic dermatosis of haematological malignancy' has been described during the course of haematological B-cell malignancies (BCM). However, its clinical evolution, histopathological features and pathogenesis remain unclear.
OBJECTIVES: To characterize this eruption and to investigate its pathogenesis and relationship with the underlying BCM.
METHODS: In this multicenter retrospective study of the French Study Group on Cutaneous Lymphomas, 37 patients with a BCM and a cutaneous eruption consisting in chronic and/or recurrent papules, papulo-vesicles and/or nodules were included. Clinical, histopathological, immunohistochemical and molecular data were reviewed.
RESULTS: No significant insect bite history or seasonal predominance was recorded. Patients had pruritic papules (81%), papulo-vesicles (43%) and nodules (38%), often predominated in the head and neck region (84%), without complete remission periods in most cases (57%). The predominant associated BCM was chronic lymphocytic leukaemia (73%). Histological and immunohistochemical review showed a dense dermal lymphocytic infiltrate predominantly composed of T lymphocytes (100%), with frequent eosinophils (77.6%); a perivascular and periadnexal (most often folliculotropic) pattern (77.6%), sometimes suggestive of a folliculotropic mycosis fungoides; clusters of tumour B cells were identified in 47% of cases using appropriate phenotyping markers. In 10/14 cases (71.4%) tested for B-cell IgH gene rearrangement, a B-cell clone was identified in skin lesions (identical to the blood clone in nine cases), whereas no T-cell clone was present.
CONCLUSION: We propose the denomination 'T-cell papulosis associated with B-cell malignancy' (TCP-BCM) for this distinctive eruption. Although resulting in various histopathological pictures, it can be easily recognized by clinicians and may be identified by informed pathologists relying on some key features. An extravasation of tumour B cells with skin-homing properties associated with a secondary, predominant, T-cell immune reaction could explain the clinicopathologic aspect and the prolonged regressive and recurrent course of the disease.

Ravela S, Valmu L, Domanskyy M, et al.
An immunocapture-LC-MS-based assay for serum SPINK1 allows simultaneous quantification and detection of SPINK1 variants.
Anal Bioanal Chem. 2018; 410(6):1679-1688 [PubMed] Related Publications
Pancreatic secretory trypsin inhibitor Kazal type 1 (SPINK1) is a 6420 Da peptide produced by the pancreas, but also by several other tissues and many tumors. Some mutations of the SPINK1 gene, like the one causing amino acid change N34S, have been shown to confer susceptibility to recurrent or chronic pancreatitis. Detection of such variants are therefore of clinical utility. So far SPINK1 variants have been determined by DNA techniques. We have developed and validated an immunocapture-liquid chromatography-mass spectrometric (IC-LC-MS) assay for the detection and quantification of serum SPINK1, N34S-SPINK1, and P55S-SPINK1. We compared this method with a time-resolved immunofluorometric assay (TR-IFMA) for serum samples and primer extension analysis of DNA samples. We used serum and DNA samples from patients with acute pancreatitis, renal cell carcinoma, or benign urological conditions. With the help of a zygosity score calculated from the respective peak areas using the formula wild-type (wt) SPINK1/(variant SPINK1 + wt SPINK1), we were able to correctly characterize the heterozygotes and homozygotes from the samples with DNA information. The score was then used to characterize the apparent zygosity of the samples with no DNA characterization. The IC-LC-MS method for SPINK1 was linear over the concentration range 0.5-1000 μg/L. The limit of quantitation (LOQ) was 0.5 μg/L. The IC-LC-MS and the TR-IFMA assays showed good correlation. The median zygosity score was 1.00 (95% CI 0.98-1.01, n = 11), 0.55 (95% CI 0.43-0.61, n = 14), and 0.05 (range 0.04-0.07, n = 3) for individuals found to be wt, heterozygous, and homozygous, respectively, for the N34S-SPINK1 variant by DNA analysis. When DNA samples are not available, this assay facilitates identification of the N34S- and P55S-SPINK1 variants also in archival serum samples.

Głuszek S, Kowalik A, Kozieł D, et al.
CTRC gene polymorphism may increase pancreatic cancer risk - preliminary study.
Pol Przegl Chir. 2017; 89(5):48-53 [PubMed] Related Publications
Pancreatic cancer is often fatal due to delayed diagnosis and treatment difficulties.
OBJECTIVE: To analyze selected SPINK1, CTRC, CFTR, and PRSS1 gene mutations in cancer tissue and blood samples of patients with pancreatic tumors.
MATERIALS AND METHOD: We enrolled 16 consecutive patients diagnosed with pancreatic tumors. We collected cancer tissue, normal pancreatic tissue, and blood samples for genetic tests. The control group consisted of 419 healthy individuals. Peripheral blood samples were collected from all study participants in EDTA-coated tubes.
RESULTS: Out of 16 patients with pancreatic tumors, 12 had pancreatic cancer on microscopic examination (mean age, 60.2 years). The CTRC polymorphism Hetero p.G60=(c.180C>T) was found in 5 patients with pancreatic cancer (41.7% vs. 18.6% in the control group). One patient with pancreatic cancer and a positive family history had the SPINK1 (p.N34S) mutation [8.3% vs. 2.9% (12/419) in the control group]. One patient with pancreatic cancer had the CTRC (p.R254W) mutation [8.3% vs. 1% (4/419) in the control group].
CONCLUSIONS: Our preliminary results show that the CTRC polymorphism p.G60= (c.180C>T) is frequent in patients with pancreatic cancer. However, further research is needed to verify our findings.

Shukla S, Cyrta J, Murphy DA, et al.
Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.
Cancer Cell. 2017; 32(6):792-806.e7 [PubMed] Free Access to Full Article Related Publications
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.

Ambrosio S, Saccà CD, Amente S, et al.
Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway.
Oncogene. 2017; 36(48):6701-6711 [PubMed] Free Access to Full Article Related Publications
Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells. At a mechanistic level, we show that LSD1 binds to the promoter region of Sestrin2 (SESN2), a critical regulator of mTORC1 activity. Pharmacological inhibition of LSD1 triggers SESN2 expression that hampers mTORC1 activity, leading to enhanced autophagy. SESN2 overexpression suffices to promote autophagy in neuroblastoma cells, while loss of SESN2 expression reduces autophagy induced by LSD1 inhibition. Our findings elucidate a mechanism whereby LSD1 controls autophagy in neuroblastoma cells through SESN2 transcription regulation, and we suggest that pharmacological targeting of LSD1 may have effective therapeutic relevance in the control of autophagy in neuroblastoma.

Lee D, Fontugne J, Gumpeni N, et al.
Molecular alterations in prostate cancer and association with MRI features.
Prostate Cancer Prostatic Dis. 2017; 20(4):430-435 [PubMed] Related Publications
BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) has been increasingly used for prostate cancer (PCa). Recent studies identified distinct molecular subclasses of PCa with recurrent genomic alterations. However, the associations between molecular alterations in PCa and characteristics on mpMRI are unknown. Therefore, the objective of this study was to investigate recurrent molecular alterations in PCa and their associations with mpMRI features.
METHODS: Sixty-two PCa nodules >0.5 cm had a preoperative mpMRI. Nodules were evaluated for ERG rearrangement, PTEN deletion, SPINK1 overexpression, SPOP mutation and CHD1 deletion. Each PCa focus was matched to the corresponding location on mpMRI. Lesions were scored by single observer according to the PI-RADSv2 scale.
RESULTS: Of the 62 nodules, 22 (35.5%) were ERG positive, 6 (9.7%) had SPINK1 overexpression, 6 (9.7%) had SPOP mutations, 4 (6.5%) had CHD1 deletions and 1 (1.6%) had PTEN deletion. All of the nodules with CHD1 deletions were not visible on mpMRI (P=0.037). All of the nodules with SPINK1 overexpression were visible on mpMRI, although the association was not statistically significant (P=0.06). There were no significant associations between any molecular alteration with the severity of the PI-RADS scores (all P>0.05).
CONCLUSIONS: This investigation represents the first description of an association between recurrent molecular alterations and the characterization of PCa nodules on mpMRI. This study can be considered hypothesis-generating for future studies to rigorously evaluate the association of specific PCa molecular subclasses with imaging features and potentially define specific subsets of PCa for which the utility of MRI is higher or lower.

Jiang P, Li Y, Poleshko A, et al.
The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network.
EBioMedicine. 2017; 22:28-43 [PubMed] Free Access to Full Article Related Publications
Genome-Wide Association Studies (GWAS) and subsequent fine-mapping studies (>50) have implicated single nucleotide polymorphisms (SNPs) located at the CCDC170/C6ORF97-ESR1 locus (6q25.1) as being associated with the risk of breast cancer. Surprisingly, our analysis using genome-wide differential allele-specific expression (DASE), an indicator for breast cancer susceptibility, suggested that the genetic alterations of CCDC170, but not ESR1, account for GWAS-associated breast cancer risk at this locus. Breast cancer-associated CCDC170 nonsense mutations and rearrangements have also been detected, with the latter being specifically implicated in driving breast cancer. Here we report that the wild type CCDC170 protein localizes to the region of the Golgi apparatus and binds Golgi-associated microtubules (MTs), and that breast cancer-linked truncations of CCDC170 result in loss of Golgi localization. Overexpression of wild type CCDC170 triggers Golgi reorganization, and enhances Golgi-associated MT stabilization and acetyltransferase ATAT1-dependent α-tubulin acetylation. Golgi-derived MTs regulate cellular polarity and motility, and we provide evidence that dysregulation of CCDC170 affects polarized cell migration. Taken together, our findings demonstrate that CCDC170 plays an essential role in Golgi-associated MT organization and stabilization, and implicate a mechanism for how perturbations in the CCDC170 gene may contribute to the hallmark changes in cell polarity and motility seen in breast cancer.

Shek FH, Luo R, Lam BYH, et al.
Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma.
Cell Oncol (Dordr). 2017; 40(5):443-456 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients.
RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/β-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in β-catenin expression (a core component of the CDH17/β-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway.
CONCLUSIONS: Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.

Ying HY, Gong CJ, Feng Y, et al.
Serine protease inhibitor Kazal type 1 (SPINK1) downregulates E-cadherin and induces EMT of hepatoma cells to promote hepatocellular carcinoma metastasis via the MEK/ERK signaling pathway.
J Dig Dis. 2017; 18(6):349-358 [PubMed] Related Publications
OBJECTIVE: To investigate serine protease inhibitor Kazal type 1 (SPINK1) expression and its influence on the prognosis of human hepatocellular carcinoma (HCC) and to explore the underlying molecular mechanisms involved.
METHODS: Altogether 80 patients with HCC who underwent curative resection were followed up for a median of 58.6 months. SPINK1 expression was detected in the primary HCC samples by immunohistochemistry. Its role in tumor invasion and metastasis was evaluated in vitro by gene silencing using a small interfering RNA-mediated approach, recombinant SPINK1 and U0126 (an inhibitor of MEK/ERK). The proteins in the MEK/ERK signaling pathway were detected by Western blot.
RESULTS: Patients with high SPINK1 expression showed poor overall survival (P = 0.0001) and recurrence-free survival (P = 0.001) compared with those with low SPINK1 expression. The suppression of SPINK1 resulted in reduced cell migration and invasion. SPINK1 overexpression was significantly associated with increased cell migration and invasion in vitro. Furthermore, SPINK1 promoted cancer cells motility and epithelial-mesenchymal transition (EMT) via the mitogen-activated protein kinase kinase (MAPK) and extracellular regulated kinase (ERK) pathway, resulting in increased vimentin expression and decreased E-cadherin expression.
CONCLUSION: SPINK1 may be an oncogene that induces EMT via the MEK/ERK pathway and is a potential target for HCC therapy.

Lotan TL, Torres A, Zhang M, et al.
Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers.
Oncotarget. 2017; 8(14):22772-22782 [PubMed] Free Access to Full Article Related Publications
A recurrent germline mutation (G84E) in the HOXB13 gene is associated with early onset and family history-positive prostate cancer in patients of European descent, occurring in up to 5% of prostate cancer families. To date, the molecular features of prostate tumors occurring in HOXB13 G84E carriers have not been studied in a large cohort of patients. We identified 101 heterozygous carriers of G84E who underwent radical prostatectomy for prostate cancer between 1985 and 2011 and matched these men by race, age and tumor grade to 99 HOXB13 wild-type controls. Immunostaining for HOXB13, PTEN, ERG, p53 and SPINK1 as well as RNA in situ hybridization for ETV1/4/5 were performed using genetically validated assays. Tumors from G84E carriers generally expressed HOXB13 protein at a level comparable to benign and wild-type glands. ETS gene expression (either ERG or ETV1/4/5) was seen in 36% (36/101) of tumors from G84E carriers compared to 68% (65/96) of the controls (p < 0.0001). PTEN was lost in 11% (11/101) of G84E carriers compared to 25% (25/99) of the controls (p = 0.014). PTEN loss was enriched among ERG-positive compared to ERG-negative tumors in both groups of patients. Nuclear accumulation of the p53 protein, indicative of underlying TP53 missense mutations, was uncommon in both groups, occurring in 1% (1/101) of the G84E carriers versus 2% (2/92) of the controls (p = NS). Taken together, these data suggest that genes other than ERG and PTEN may drive carcinogenesis/progression in the majority of men with germline HOXB13 mutations.

Zhu M, Geng L, Shen W, et al.
Exome-Wide Association Study Identifies Low-Frequency Coding Variants in 2p23.2 and 7p11.2 Associated with Survival of Non-Small Cell Lung Cancer Patients.
J Thorac Oncol. 2017; 12(4):644-656 [PubMed] Related Publications
INTRODUCTION: A growing body of evidence has suggested that low-frequency or rare coding variants might have strong effects on the development and prognosis of cancer. Here, we aim to assess the role of low-frequency and rare coding variants in the survival of NSCLC in Chinese populations.
METHODS: We performed an exome-wide scan of 247,870 variants in 1008 patients with NSCLC and replicated the promising variants by using imputed genotype data of The Cancer Genome Atlas (TCGA) with a Cox regression model. Gene-based and pathway-based analysis were also performed for nonsynonymous or splice site variants. Additionally, analysis of gene expression data in the TCGA was used to increase the reliability of candidate loci and genes.
RESULTS: A low-frequency missense variant in chaperonin containing TCP1 subunit 6A gene (CCT6A) (rs33922584: adjusted hazard ratio [HR
CONCLUSION: These results provided more evidence for the important role of low-frequency or rare variants in the survival of patients with NSCLC.

Hass HG, Vogel U, Scheurlen M, Jobst J
Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.
Anticancer Res. 2016; 36(10):5087-5095 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation.
MATERIALS AND METHODS: DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples.
RESULTS: Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis.
CONCLUSION: It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.

Midha S, Sreenivas V, Kabra M, et al.
Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer.
Pancreas. 2016; 45(10):1478-1484 [PubMed] Related Publications
OBJECTIVE: To study if chronic pancreatitis (CP) is a risk factor for pancreatic cancer.
METHODS: Through a cohort and a case-control study design, CP and other important risk factors including smoking, diabetes, alcohol, obesity, and genetic mutations were studied for their association with pancreatic cancer.
RESULTS: In the cohort study, 402 patients with CP were included. During 3967.74 person-years of exposure, 5 of the 402 patients (4 idiopathic CP, 1 hereditary CP) developed pancreatic cancer after 16.60 ± 3.51 years of CP. The standardized incidence ratio was 121. In the case-control study, 249 pancreatic cancer patients and 1000 healthy controls were included. Of the 249 patients with pancreatic cancer, 24 had underlying idiopathic CP, and none had alcoholic pancreatitis. SPINK1 gene mutation was present in 16 of 26 patients with idiopathic CP who had pancreatic cancer. Multivariable analysis showed CP (odds ratio [OR], 97.67; 95% confidence interval [CI], 12.69-751.36), diabetes (>4 years duration) (OR, 3.05; 95% CI, 1.79-5.18), smoking (OR, 1.93; 95% CI, 1.38-2.69) as significant risk factors for pancreatic cancer. The population attributable risk was 9.41, 9.06, and 9.50 for diabetes, CP, and smoking, respectively.
CONCLUSIONS: Genetically determined CP but not alcoholic CP is a strong risk factor for pancreatic cancer.

Huang KC, Evans A, Donnelly B, Bismar TA
SPINK1 Overexpression in Localized Prostate Cancer: a Rare Event Inversely Associated with ERG Expression and Exclusive of Homozygous PTEN Deletion.
Pathol Oncol Res. 2017; 23(2):399-407 [PubMed] Related Publications
SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n = 218 and validation n = 129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated. SPINK1 was expressed in 15.3 % and 10.9 % of cases in the discovery and validation cohort, respectively. SPINK expression was observed in 5.56 % of high-grade prostatic intraepithelial neoplasia and 1.1 % of adjacent morphologically benign prostatic glands. SPINK1 and ERG expression were almost exclusive, with only 1.0 % of the cases co-expressing both in the same core sample. SPINK1 interfocal and within-core heterogeneity was noted in 29.2 % and 64.6 % of cases, respectively. SPINK1 expression was not significantly associated with PTEN deletion in the two cohorts (p = 0.871 for discovery cohort and p = 0.293 for validation cohort). While SPINK1 expression did occur with hemizygous PTEN deletion, there was a complete absence of SPINK1 expression in PCA showing homozygous PTEN deletion, which was confirmed in the validation cohort (p = 0.02). Despite SPINK1's association with higher Gleason score (>7) (p = 0.02), it was not associated with other pathological parameters or biochemical recurrence post-radical prostatectomy. We documented absolute exclusivity between SPINK1 overexpression and homozygous PTEN deletion in localized PCA. SPINK1 and ERG expressions are exclusive events in PCA. SPINK1 is not of added prognostic value in localized PCA.

Kim H, Skowronski J, Den RB
Prognostic outlier genes for enhanced prostate cancer treatment.
Future Oncol. 2017; 13(3):249-261 [PubMed] Related Publications
AIM: To review the current landscape of outlier genes in the field of prostate cancer.
METHODS: A comprehensive review was performed.
RESULTS: Prostate cancer continues to be a significant worldwide health issue. In the era of personalized medicine, more emphasis is being placed on the ability to determine the timing, intensity and type of treatment, according to each patient's unique disease. Several commercial tests are available to determine the risk of aggressive prostate cancer based on genomic biomarkers and gene expression. Outlier genes represent a form of cancer classification that focuses on bimodal expression of a gene in a specific subset of patients. Outlier genes identified in prostate cancer include TMPRSS2-ERG, SPINK1, ScHLAP1, NVL, SMC4 and SQLE.
CONCLUSION: Classifying patient prostate cancers by outlier genes may allow for individualized cancer therapies and improved cancer therapy outcomes.

Rotondi M, Coperchini F, Awwad O, et al.
Effect of Interferon-γ on the Basal and the TNFα-Stimulated Secretion of CXCL8 in Thyroid Cancer Cell Lines Bearing Either the RET/PTC Rearrangement Or the BRAF V600e Mutation.
Mediators Inflamm. 2016; 2016:8512417 [PubMed] Free Access to Full Article Related Publications
CXCL8 displays several tumor-promoting effects. Targeting and/or lowering CXCL8 concentrations within the tumor microenvironment would produce a therapeutic benefit. Aim of this study was to test the effect of IFNγ on the basal and TNFα-stimulated secretion of CXCL8 in TCP-1 and BCPAP thyroid cancer cell lines (harboring RET/PTC rearrangement and BRAF V600e mutation, resp.). Cells were incubated with IFNγ (1, 10, 100, and 1000 U/mL) alone or in combination with TNF-α (10 ng/mL) for 24 hours. CXCL8 and CXCL10 concentrations were measured in the cell supernatants. IFNγ inhibited in a dose-dependent and significant manner both the basal (ANOVA F: 22.759; p < 0.00001) and the TNFα-stimulated (ANOVA F: 15.309; p < 0.00001) CXCL8 secretions in BCPAP but not in TPC-1 cells (NS). On the other hand, IFNγ and IFNγ + TNF-α induced a significant secretion of CXCL10 in both BCPAP (p < 0.05) and TPC-1 (p < 0.05) cells. Transwell migration assay showed that (i) CXCL8 increased cell migration in both TPC-1 and BCPAP cells; (ii) IFNγ significantly reduced the migration only of BCPAP cells; and (iii) CXCL8 reverted the effect of IFNγ. These results constitute the first demonstration that IFNγ inhibits CXCL8 secretion and in turn the migration of a BRAF V600e mutated thyroid cell line.

Yaming P, Urs AB, Saxena A, Zuberi M
Roles of CYP1A1 and CYP2E1 Gene Polymorphisms in Oral Submucous Fibrosis.
Asian Pac J Cancer Prev. 2016; 17(7):3335-40 [PubMed] Related Publications
BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous condition with a 4 to13% malignant transformation rate. Related to the habit of areca nut chewing it is mainly prevalent in Southeast Asian countries where the habit of betel quid chewing is frequently practised. On chewing, alkaloids and polyphenols are released which undergo nitrosation and give rise to Nnitrosamines which are cytotoxic agents. CYP450 is a microsomal enzyme group which metabolizes various endogenous and exogenous chemicals including those released by areca nut chewing. CYP1A1 plays a central role in metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes nitrosamines and tannins. Polymorphisms in genes that code for these enzymes may alter their expression or function and may therefore affect an individuals susceptibility regarding OSF and oral cancer. The present study was therefore undertaken to investigate the association of polymorphisms in CYP1A1 m2 and CYP2E1 (RsaI/PstI) sites with risk of OSF among areca nut chewers in the Northern India population. A total of 95 histopathologically confirmed cases of OSF with history of areca nut chewing not less than 1 year and 80, age and sex matched controls without any clinical signs and symptoms of OSF with areca nut chewing habit not less than 1 year were enrolled. DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCRRFLP method. Gene polymorphism of CYP1A1 at NcoI site was observed to be significantly higher (p = 0.016) in cases of OSF when compared to controls. Association of CYP1A1 gene polymorphism at NcoI site and the risk of OSF (Odd's Ratio = 2.275) was also observed to be significant. However, no such association was observed for the CYP2E1 gene polymorphism (Odd's Ratio = 0.815). Our results suggest that the CYP1A1 gene polymorphism at the NcoI site confers an increased risk for OSF.

Moran RA, Klapheke R, Jalaly NY, et al.
Metastatic pancreatic adenocarcinoma associated with chronic calcific pancreatitis and a heterozygous SPINK1 N34S mutation.
Pancreatology. 2016 Sep-Oct; 16(5):869-72 [PubMed] Related Publications
Contrary to patients with a cationic trypsinogen gene (PRSS1) mutations, Serine protease inhibitor Kazal-type 1 (SPINK1) heterozygote gene mutation carriers have a very low penetrance for acute, acute recurrent and/or chronic pancreatitis. Despite this, heterozygote SPINK 1 gene mutation patients have a similar age of onset of pancreatitis as PRSS 1 gene mutation patients. While the substantially elevated risk of pancreatic cancer in patients with PRSS1 gene mutations with chronic pancreatitis has been well established, little is known about the risk of pancreatic cancer in SPINK 1 gene mutation carriers with pancreatitis. We describe a case of malignant pancreatic cancer diagnosed in a young patient with chronic pancreatitis who is a SPINK 1 heterozygote gene mutation carrier. The risk of pancreatic cancer in gene mutation patients with chronic pancreatitis, in addition to screening options and management options for these patients is discussed.

Volante M, Tota D, Giorcelli J, et al.
Androgen deprivation modulates gene expression profile along prostate cancer progression.
Hum Pathol. 2016; 56:81-8 [PubMed] Related Publications
Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and initially induces tumor regression, but invariably results in castration-resistant prostate cancer through various mechanisms, incompletely discovered. Our aim was to analyze the dynamic modulation, determined by ADT, of the expression of selected genes involved in the pathogenesis and progression of prostate cancer (TMPRSS2:ERG, WNT11, SPINK1, CHGA, AR, and SPDEF) using real-time polymerase chain reaction in a series of 59 surgical samples of prostate carcinomas, including 37 cases preoperatively treated with ADT and 22 untreated cases, and in 43 corresponding biopsies. The same genes were analyzed in androgen-deprived and control LNCaP cells. Three genes were significantly up-modulated (WNT11 and AR) or down-modulated (SPDEF) in patients treated with ADT versus untreated cases, as well as in androgen-deprived LNCaP cells. The effect of ADT on CHGA gene up-modulation was almost exclusively detected in cases positive for the TMPRSS2:ERG fusion. The correlation between biopsy and surgical samples was poor for most of the tested genes. Gene expression analysis of separate tumor areas from the same patient showed an extremely heterogeneous profile in the 6 tested cases (all untreated). In conclusion, our results strengthened the implication of ADT in promoting a prostate cancer aggressive phenotype and identified potential biomarkers, with special reference to the TMPRSS2:ERG fusion, which might favor the development of neuroendocrine differentiation in hormone-treated patients. However, intratumoral heterogeneity limits the use of gene expression analysis as a potential prognostic or predictive biomarker in patients treated with ADT.

Zheng YC, Yu B, Chen ZS, et al.
TCPs: privileged scaffolds for identifying potent LSD1 inhibitors for cancer therapy.
Epigenomics. 2016; 8(5):651-66 [PubMed] Related Publications
Since the first lysine-specific demethylase (KDM), lysine-specific demethylase 1 (LSD1), was characterized in 2004, several families of KDMs have been identified. LSD1 can specifically demethylate H3K4me1/2, H3K9me1/2 as well as some nonhistone substrates. It has been demonstrated to be an oncogene as well as a drug target. Hence, tens of small-molecule LSD1 inhibitors have been designed, synthesized and applied for cancer treatment. However, the two LSD1 inhibitors that have been advanced into early phase clinical trials are trans-2-phenylcyclopropylamine (TCP) derivatives, which indicate that TCP is a druggable scaffold for LSD1 inhibitor. Here, we review the design, synthesis and properties of reported TCP-based LSD1 inhibitors as well as their biological roles.

Bassiouni R, Nemec KN, Iketani A, et al.
Chaperonin Containing TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide.
Clin Cancer Res. 2016; 22(17):4366-79 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p.
EXPERIMENTAL DESIGN: Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p.
RESULTS: Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTβ, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTβ levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTβ and higher levels of the chaperone.
CONCLUSIONS: Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. Clin Cancer Res; 22(17); 4366-79. ©2016 AACR.

Kaffenberger SD, Barbieri CE
Molecular subtyping of prostate cancer.
Curr Opin Urol. 2016; 26(3):213-8 [PubMed] Free Access to Full Article Related Publications
PURPOSE OF REVIEW: The recent publication of The Cancer Genome Atlas molecular taxonomy of primary prostate cancer highlights the increased understanding of the genomic basis of human prostate cancer, but also emphasizes the complexity and heterogeneity of prostate cancer.
RECENT FINDINGS: Seven molecular subclasses have been defined on the basis of early genomic alterations, which are largely mutually exclusive.
SUMMARY: We review the recent advances in the genomic understanding of human prostate cancer, with focus on molecular subclassification. Broadly, prostate cancer can be classified based upon whether specific genomic rearrangements, such as the Transmembrane Protease, Serine 2-ETS-related gene fusion occur or whether specific alterations such as Speckle-type POZ protein and forkhead box A1 mutations occur. The molecular drivers remain to be identified in a further quarter of human prostate cancers. Depending upon the molecular subclassification and the coincident genomic alterations, specific clinical insights can be gained from this information, including associations with pathologic factors, race, and prognosis, as well as the possibility for future precision therapies.

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