Antonacopoulou Anna, Kottorou Anastasia E, Dimitrakopoulos Foteinos-Ioannis, Marousi Stella, Kalofonou Foteini, Koutras Angelos, Makatsoris Thomas, Tzelepi Vassiliki, Kalofonos Haralabos P
Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, Medical School, University of Patras, Patras, Greece.
Clinical and Molecular Oncology Laboratory, Division of Oncology, Department of Medicine, Medical School, University of Patras, Patras, Greece.
Transl Oncol. 2021 Jan;14(1):100912. doi: 10.1016/j.tranon.2020.100912. Epub 2020 Oct 16.
The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family of transcription factors plays an important role in immune responses and cancer development and progression. We have focused on NF-κB2 and RELB of the alternative pathway of NF-κB, which remains largely underexplored in colorectal cancer (CRC). We found that NF-κB2 and RELB protein levels were upregulated in tumour and surrounding stromal tissue compared to distant non-neoplastic tissue (NN) and associated stroma (p<0.001 in all associations). Moreover, low RELB protein expression was associated with decreased overall survival (p = 0.032). Lower RELB gene expression levels were observed in tumour compared to NN tissue (p = 0.003) and were associated with shorter time to progression (TTP) (p = 0.025). NF-κB2 gene expression levels were similar in tumour and NN tissue, but higher tumour levels were prognostic for improved survival (p = 0.038) and TTP (p<0.001). We also assessed the significance of two NF-κB2 genetic polymorphisms, rs12769316 and rs7897947. Both polymorphisms were associated with lymph node infiltration (p = 0.045 and p = 0.009, respectively). In addition, rs12769316 AA homozygotes relapsed less often compared to G allele carriers (p = 0.029). Moreover, rs7897947 allele frequencies differed significantly between CRC patients and healthy controls (p<0.001) and the minor allele (G) was associated with reduced risk for developing CRC (p<0.001, OR: 0.527, 95% CI: 0.387-0.717). In conclusion, the alternative NF-κB pathway appears deregulated in CRC. Moreover, NF-κB2 and RELB expression levels seem to be significant for the clinical outcome of CRC patients and rs7897947 appears to be a risk factor for CRC development.
活化B细胞的核因子κ轻链增强子（NF-κB）转录因子家族在免疫反应以及癌症的发生和发展过程中发挥着重要作用。我们聚焦于NF-κB替代途径中的NF-κB2和RELB，在结直肠癌（CRC）中，该途径在很大程度上仍未得到充分研究。我们发现，与远处非肿瘤组织（NN）及相关基质相比，肿瘤组织和周围基质组织中NF-κB2和RELB蛋白水平上调（所有关联中p<0.001）。此外，RELB蛋白低表达与总生存期降低相关（p = 0.032）。与NN组织相比，肿瘤组织中RELB基因表达水平较低（p = 0.003），且与较短的疾病进展时间（TTP）相关（p = 0.025）。肿瘤组织和NN组织中NF-κB2基因表达水平相似，但肿瘤组织中较高的水平对生存期改善（p = 0.038）和TTP（p<0.001）具有预后意义。我们还评估了两种NF-κB2基因多态性rs1276931和rs7897947的意义。两种多态性均与淋巴结浸润相关（分别为p = 0.045和p = 0.009）。此外，与G等位基因携带者相比，rs12769316 AA纯合子复发频率较低（p = 0.029）。此外，CRC患者与健康对照之间rs7897947等位基因频率存在显著差异（p<0.001），次要等位基因（G）与CRC发生风险降低相关（p<0.001，OR：0.527，95%CI：0.387 - 0.717）。总之，在CRC中，NF-κB替代途径似乎失调。此外，NF-κB2和RELB表达水平似乎对CRC患者的临床结局具有重要意义，且rs7897947似乎是CRC发生的一个风险因素。
