JAB 1 ‐ STAT 3 activation loop is associated with recurrence following 5 ‐ fluorouracil ‐ based adjuvant chemotherapy in human colorectal cancer

Jun activation domain-binding protein 1 (JAB1) has been shown to have multiple roles in tumorigenesis, including the degradation of tumor suppressor proteins such as p53, Smad7, Runx3 and the cyclin-dependent kinase inhibitor p27Kip1, and the activation of oncogenic transcription factors, such as c-Jun and hypoxia-inducible factor-1α. In addition, our previous study revealed that JAB1 positively regulates signal transducer and activator of transcription 3 (STAT3) DNA-binding activity in human colon cancer cells. In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop. Furthermore, high JAB1 expression is associated with a poor prognosis in numerous malignant carcinomas. However, the association between JAB1 expression and prognosis in colorectal cancer remains unclear. The aim of the present study was to elucidate the association between JAB1 and STAT3 expression and recurrence in colorectal cancer. In the present study, it was found that high JAB1 expression in primary colorectal cancer tissues is an independent predictor of recurrence following 5‐fluorouracil (5‐FU)‐based adjuvant chemotherapy in colorectal cancer patients, and that high expression of both JAB1 and STAT3 in primary colorectal cancer tissues is associated with a lower recurrence-free survival rate following 5‐FU‐based adjuvant chemotherapy compared to high expression of only JAB1 or STAT3. Overall, these results suggest that JAB1 is a novel predictive marker of recurrence following 5‐FU‐based adjuvant chemotherapy in colorectal cancer patients, and that the JAB1-STAT3 activation loop may be a potential therapeutic target in recurrent colorectal cancer following 5‐FU‐based adjuvant chemotherapy. Introduction Jun activation domain-binding protein 1 (JAB1) was originally identified as a co‐activator of c‐Jun that stabilizes its DNA-binding through protein-protein interaction (1). Subsequently, JAB1 was found to interact with numerous other proteins, affecting protein stability and transcriptional activity of its interacting partner proteins, which are involved in the regulation of the cell cycle, signal transduction and DNA repair (2). JAB1 has an important role in tumorigenesis, inactivating tumor suppressor proteins and activating oncogenic transcription factors. JAB1 facilitates the translocation of tumor suppressor proteins, including p53 (3,4), Smad7 (5), Runx3 (6) and the cyclin-dependent kinase inhibitor p27Kip1 (7,8), from the nucleus to the cytoplasm, where they are subsequently degraded in the proteasome. JAB1 is also a transcriptional co-activator of c-Jun (1), hypoxia-inducible factor-1α (9,10) and signal transducer and activator of transcription 3 (STAT3) (11). JAB1 is positively regulated by oncogenic transcription factors STAT3 and β-catenin/TCF-4 (12,13). STAT3 positively regulates JAB1 expression through its binding to the JAB1 promoter (12), and HER2 increases JAB1 expression through the binding of β-catenin/TCF-4 to the JAB1 promoter in human breast cancer cells (13). These findings suggest that JAB1 is a target gene of STAT3 and β-catenin/TCF-4. Overall, with our recent findings that JAB1 positively regulates STAT3 DNA-binding activity in human colon cancer cells (11), the results of these studies suggest that the JAB1-STAT3 activation loop exists in human colorectal cancer cells. Furthermore, high JAB1 expression has been reported to be associated with poor prognosis in numerous malignant carcinomas, including ovarian cancer (14,15), oral squamous cell carcinoma (16), laryngeal squamous cell carcinoma (17), hepatocellular carcinoma (18), glioma (19), soft-tissue sarcoma (20), pancreatic cancer (21), esophageal squamous cell carcinoma (22), lung cancer (23) and non-Hodgkin's lymphoma (24). However, the association between JAB1 expression and prognosis in colorectal cancer remains largely unknown. The objectives of the present study were therefore to elucidate the associations between JAB1 and STAT3 expression and recurrence in colorectal cancer. JAB1‐STAT3 activation loop is associated with recurrence following 5‐fluorouracil‐based adjuvant chemotherapy in human colorectal cancer NARUJI KUGIMIYA, ARATA NISHIMOTO, TOHRU HOSOYAMA, KOJI UENO, YOSHIHIRO TAKEMOTO, EIJIRO HARADA, TADAHIKO ENOKI and KIMIKAZU HAMANO Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755‐8505, Japan Received December 28, 2015; Accepted July 3, 2017 DOI: 10.3892/ol.2017. 6994 Correspondence to: Dr Arata Nishimoto, Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1‐1‐1 Minami‐Kogushi, Ube, Yamaguchi 755‐8505, Japan E-mail: anishimo@yamaguchi-u.ac. jp