Abstract Background: We previously reported that activation of TNF-α results in upregulation of NF-κB and nuclear translocation of BCL3 and BCL10 in breast cancer cell line and lymphoma cell line (J Biol Chem 2006;281:167-75, Blood 2008;112:2927-34). Furthermore, we recently demonstrated that BCL10 plays an important role in controlling the growth of cervical cancer cells through NF-κB dependent cyclin D1 regulation (Gynecol Oncol 2012;126:245-51). Since NF-κB activation has been shown to occur in the pathogenesis of pancreatic cancer, we sought to investigate whether BCL10-signaling possesses clinical significance in relation to pancreatic cancer. Methods: Three pancreatic cancer cell lines (PANC-1, AsPC-1, and BxPC-3) were used in this study. Cell cycle was analyzed by flow cytometry. The expression of protein and mRNA of BCL10- and NF-κB- related signaling was assessed by immunoblotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The DNA-binding activity of NF-κB was determined by the luciferase assay. The expression of BCL10, and NF-κB in tumor cells from recurrent, locally advanced, and metastatic pancreatic patients who received chemotherapy was examined using immunohistochemical staining. Results: We transfected three pancreatic cancer cell lines with BCL10 small interfering RNA (siRNA), and discovered that the down-regulation of BCL10 inhibited the viability of these pancreatic cancer cells through the G1 arrest. BCL10 siRNA treatment inhibited the expression of p-IKKβ and p-IκB, and nuclear BCL3 translocation, and also down-regulated NF-κB activation and its downstream cell cycle proteins, c-Myc, and cyclin B1. The results of qRT-PCR showed that BCL10 siRNA treatment inhibited the mRNA expression levels of BCL10, BCL3, c-Myc, and cyclin B1. Our results reveal that patients with nuclear BCL10 expression had a worse median overall survival than those without (7.9 months versus 16.9 months, p = 0.007). Furthermore, nuclear expression of BCL10 was closely associated with nuclear BCL3 expression (p < 0.001), and NF-κB activation (p < 0.001). Conclusions: Our findings indicate that nuclear BCL10 plays an important role in controlling the growth and progression of pancreatic cancer cells through NF-κB-related signaling pathway. Citation Format: Sung-Hsin Kuo, Shih-Hung Yang, Kun-Huei Yeh, Pei-Yen Yeh, Yu-Wen Tien, Hsiao-Wei Lee, Li-Tzong Chen, Ann-Lii Cheng. Nuclear expression of BCL10 has a role in the regulation of cell growth and progression of pancreatic cancer through the activation of NF-κB-related signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4217. doi:10.1158/1538-7445.AM2014-4217