{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPINK1 encodes a secreted serine protease inhibitor whose deregulated expression has profound effects in several cancers. In prostate cancer, for example, SPINK1 overexpression—observed exclusively in subsets of ETS‐negative tumors—promotes cell proliferation, invasion, and intravasation, thereby correlating with aggressive tumor behavior and early biochemical recurrence. In addition, SPINK1 expression has been associated with particular histologic variants of prostate carcinoma and with altered hormone responsiveness, while emerging evidence also indicates that SPINK1 (often referred to as tumor‐associated trypsin inhibitor, TATI) contributes to poor clinical outcomes in colorectal, lung, and even breast cancers by fostering chemoresistance and cellular plasticity via mechanisms including EGFR activation and epithelial–endothelial transition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the pancreas SPINK1 serves as a critical safeguard against autodigestion by inhibiting premature trypsinogen activation. Mutations in SPINK1—notably the common N34S variant along with several other missense changes—have been linked to a spectrum of pancreatic disorders, including hereditary, idiopathic, and tropical calcific pancreatitis as well as fibrocalculous pancreatic diabetes. A number of genetic studies, often conducted alongside analyses of PRSS1 and CFTR variants, have demonstrated that an impaired SPINK1 inhibitory function predisposes individuals to uncontrolled trypsin activity and subsequent pancreatic injury. Collectively, these investigations underscore SPINK1’s dual role as both a causative mutation and a disease‐modifier in pancreatitis across diverse ethnic and etiologic backgrounds."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established roles in oncogenesis and pancreatitis, SPINK1 has also emerged as a multifaceted player in stress and injury responses. Recent investigations have identified SPINK1 as a senescence‐associated secretory phenotype (SASP) factor produced by stromal cells exposed to genotoxic stress. This extracellular SPINK1 not only reinforces cancer cell aggressiveness by stimulating migratory and invasive programs but also modulates protease cascades in other pathological settings such as diabetic nephropathy. These findings highlight SPINK1’s versatile involvement in cellular signaling networks that impact disease progression and therapy resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Scott A Tomlins, Daniel R Rhodes, Jianjun Yu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mod Pathol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/modpathol.2009.79"}], "href": "https://doi.org/10.1038/modpathol.2009.79"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19465903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19465903"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Richard Flavin, Andreas Pettersson, Whitney K Hendrickson, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gutjnl-2011-300645"}], "href": "https://doi.org/10.1136/gutjnl-2011-300645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22427236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22427236"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Alexander Schneider, Jessica Larusch, Xiumei Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2010.10.045"}], "href": "https://doi.org/10.1053/j.gastro.2010.10.045"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20977904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20977904"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "F U Weiss, P Simon, N Bogdanova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gut.2005.064808"}], "href": "https://doi.org/10.1136/gut.2005.064808"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15987793"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15987793"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Marie-Pierre Audrézet, Jian-Min Chen, Cedric Le Maréchal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ejhg.5200786"}], "href": "https://doi.org/10.1038/sj.ejhg.5200786"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11938439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11938439"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Alexander Schneider, Amitabh Suman, Livio Rossi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/gast.2002.36059"}], "href": "https://doi.org/10.1053/gast.2002.36059"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12360464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12360464"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Elie Aoun, Chung-Chou H Chang, Julia B Greer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0002003"}], "href": "https://doi.org/10.1371/journal.pone.0002003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18414673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18414673"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "G R Chandak, M M Idris, D N Reddy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gut.2003.026526"}], "href": "https://doi.org/10.1136/gut.2003.026526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15082592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15082592"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Shallu Midha, Rajni Khajuria, Shivaram Shastri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gut.2009.191239"}], "href": "https://doi.org/10.1136/gut.2009.191239"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20551465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20551465"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Steven Keiles, Anja Kammesheidt "}, {"type": "b", "children": [{"type": "t", "text": "Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pancreas (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/01.mpa.0000232014.94974.75"}], "href": "https://doi.org/10.1097/01.mpa.0000232014.94974.75"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17003641"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17003641"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Emmanuelle Masson, Jian-Min Chen, Marie-Pierre Audrézet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0073522"}], "href": "https://doi.org/10.1371/journal.pone.0073522"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23951356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23951356"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Niels Teich, Nadine Bauer, Joachim Mössner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Gastroenterol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1572-0241.2002.05467.x"}], "href": "https://doi.org/10.1111/j.1572-0241.2002.05467.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11866271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11866271"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Orsolya Király, Thomas Wartmann, Miklós Sahin-Tóth "}, {"type": "b", "children": [{"type": "t", "text": "Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gut.2006.115725"}], "href": "https://doi.org/10.1136/gut.2006.115725"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17525091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17525091"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Zahid Hassan, Viswananthan Mohan, Liaquat Ali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/342731"}], "href": "https://doi.org/10.1086/342731"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12187509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12187509"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "E Kereszturi, O Király, M Sahin-Tóth "}, {"type": "b", "children": [{"type": "t", "text": "Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gut (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/gut.2008.164947"}], "href": "https://doi.org/10.1136/gut.2008.164947"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18978175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18978175"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Alexander Schneider, Roland H Pfützer, M Michael Barmada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dig Dis Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1023/a:1023768829772"}], "href": "https://doi.org/10.1023/a:1023768829772"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12822871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12822871"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Agnieszka Sobczyńska-Tomaszewska, Daniel Bak, Beata Oralewska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pediatr Gastroenterol Nutr (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/01.mpg.0000232570.48773.df"}], "href": "https://doi.org/10.1097/01.mpg.0000232570.48773.df"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16954950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16954950"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Venkata Muddana, Janette Lamb, Julia-B Greer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.14.4486"}], "href": "https://doi.org/10.3748/wjg.14.4486"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18680227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18680227"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Giulia Martina Cavestro, Raffaella Alessia Zuppardo, Simone Bertolini, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Association of SPINK1 gene mutation and CFTR gene polymorphisms in patients with pancreas divisum presenting with idiopathic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Gastroenterol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MCG.0b013e3181a4e772"}], "href": "https://doi.org/10.1097/MCG.0b013e3181a4e772"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19593166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19593166"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "P Felderbauer, W Klein, K Bulut, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Gastroenterol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00365520510024214"}], "href": "https://doi.org/10.1080/00365520510024214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16497624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16497624"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Marko Lempinen, Annukka Paju, Esko Kemppainen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations N34S and P55S of the SPINK1 gene in patients with chronic pancreatitis or pancreatic cancer and in healthy subjects: a report from Finland."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Gastroenterol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00365520510011560"}], "href": "https://doi.org/10.1080/00365520510011560"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15764155"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15764155"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Andrea L Ferreira Bernardino, Dulce Reis Guarita, Carlos Barros Mott, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JOP (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14526128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14526128"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "H Witt "}, {"type": "b", "children": [{"type": "t", "text": "Gene mutations in children with chronic pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pancreatology (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000055843"}], "href": "https://doi.org/10.1159/000055843"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12120220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12120220"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Peter Felderbauer, Elias Karakas, Volker Fendrich, et al. 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