title: Inactivation of JNK2 as carcinogenic factor in colitis-associated and sporadic colorectal carcinogenesis.
abstract: We recently reported that dysregulated c-Jun N-terminal kinases (JNK) activity causes defective cell cycle checkpoint control, inducing neoplastic transformation in a cellular ulcerative colitis (UC) model. In the quiescent chronic phase of UC, p-p54 JNK was down-regulated and p-p46 JNK was up-regulated. Both were up-regulated in the acute phase. Consequently, increased p21WAF1 and γ-H2AX, two JNK-regulated proteins, induced cell cycle arrest. Their down-regulation led to checkpoint override, causing increased proliferation and undetected DNA damage in quiescent chronic phase, all characteristics of tumorigenesis. We investigated expression of p-JNK2, p-JNK1-3, p21WAF1, γ-H2AX and Ki67 by immunohistochemistry in cases of quiescent UC (QUC), active UC (AUC), UC-dysplasia and UC-related colorectal carcinoma (UC-CRC). Comparison was made to normal healthy colorectal mucosa, sporadic adenoma and colorectal carcinoma (CRC), diverticulitis and Crohns disease (CD). We found p-JNK2 up-regulation in AUC and its early down-regulation in UC-CRC and CRC carcinogenesis. With down-regulated p-JNK2, p21WAF1 was also decreased. Ki67 was inversely expressed, showing increased proliferation early in UC-CRC and CRC carcinogenesis. p-JNK1-3 was increased in AUC and QUC. Less increased γ-H2AX in UC-CRC compared to CRC gave evidence that colitis-triggered inflammation masks DNA damage, thus contributing to neoplastic transformation. We hypothesize that JNK-dependent cell cycle arrest is important in AUC, while chronic inflammation causes dysregulated JNK activity in quiescent phase that may contribute to checkpoint override, promoting UC carcinogenesis. We suggest restoring p-JNK2 expression as a novel therapeutic strategy to early prevent the development of UC-related cancer.
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Lessel
authors.affiliation: Colorectal Cancer Genetics, Centre for Genomic and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, E1 2A London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Jechorek
authors.affiliation: Department of Pathology, 22339 Hamburg, Germany.|Academic Department of Histopathology, St. Mark's Hospital, HA1 3UJ Harrow, Middlesex, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guenther
authors.affiliation: Department of Biometrics and Medical Informatics, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
authors.forename: Friedrich-Wilhelm
authors.initials: FW
authors.lastname: Roehl
authors.affiliation: Department of Pathology, 22339 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Poehlmann-Nitsche
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003092:Colitis / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics* / Q000378:metabolism; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D055815:Young Adult
chemical_list: D015415:Biomarkers; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D019394:Ki-67 Antigen; D048056:Mitogen-Activated Protein Kinase 9