Contribution of nuclear BCL10 expression to tumor progression and poor prognosis of advanced and/or metastatic pancreatic ductal adenocarcinoma by activating NF-\u03baB-related signaling

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

doi:10.1186/s12935-021-02143-z

Abstract

BackgroundWe 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 materialsWe 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.ResultsWe 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).ConclusionNuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

Highlights

The majority of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed when the cancer becomes un-resectable and metastatic [1, 2]
We revealed that BCL10 shRNA transfected (shBCL10) transfection caused cytoplasmic translocation of B-cell CLL/lymphoma 10 (BCL10) from the nuclei, inhib‐ ited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines
Previous evidence has demonstrated that KRAS mutation can activate the KRAS protein, which further triggers a cascade of survival signaling, including phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin, p38 mitogen-activated protein kinase (MAPK), extracellular signal- regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Nuclear factor-κappa B (NF-κB), and promotes proliferation, migration, invasiveness, and causes further progression and poor prognosis of PDAC [30, 31]

Summary

Introduction

The majority of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed when the cancer becomes un-resectable and metastatic [1, 2]. Previous studies have demonstrated that sonic hedgehog (Shh) ligands facilitate cell proliferation of PDAC through triggering nuclear factor (NF)-κB [11, 12]. Our previous work showed that nuclear expression of NF-κB or Gli (a determinant of Shh signaling) was associated with poor overall survival (OS) of patients with advanced and metastatic PDAC after commencing chemotherapy [13]. These findings suggested that proinflammatory cytokines or growth factors can activate NF-κB signaling in stromal or cancer cells of PDAC though autocrine or paracrine loop. We assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC)

Methods

Results

Discussion

Conclusion