Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-κB-related signaling

Sung-Hsin Kuo; Shih-Hung Yang; Ming-Feng Wei; Hsiao-Wei Lee; Yu-Wen Tien; Ann-Lii Cheng; Kun-Huei Yeh

doi:10.1186/s12935-021-02143-z

Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-κB-related signaling

Cancer Cell Int. 2021 Aug 19;21(1):436. doi: 10.1186/s12935-021-02143-z.

Authors

Sung-Hsin Kuo^{1

2

3}, Shih-Hung Yang^{1

2

3

4}, Ming-Feng Wei^{1

3}, Hsiao-Wei Lee^{1

3}, Yu-Wen Tien⁵, Ann-Lii Cheng^{1

6

2

3

7}, Kun-Huei Yeh^{8

9

10

11}

Affiliations

¹ Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan S Rd, Taipei, Taiwan.
² Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
³ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
⁵ Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁶ Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁷ Department of Oncology, National Taiwan University Cancer Center, National Taiwan University College of Medicine, Taipei, Taiwan.
⁸ Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan S Rd, Taipei, Taiwan. khyeh@ntu.edu.tw.
⁹ Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan. khyeh@ntu.edu.tw.
¹⁰ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. khyeh@ntu.edu.tw.
¹¹ Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. khyeh@ntu.edu.tw.

Abstract

Background: We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC).

Method and materials: We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining.

Results: We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p < 0.001), and patients with nuclear BCL10 expression had the worse median overall survival than those without nuclear BCL10 expression (6.90 months versus 9.53 months, p = 0.019).

Conclusion: Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

Keywords: BCL10; NF-κB; Pancreatic cancer; Prognosis.

Abstract

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