IKKε and TBK1 expression in gastric cancer.

Seung Eun Lee,Jeeyun Lee,Kyoung-Mee Kim,Junhun Cho,Mineui Hong

doi:10.18632/oncotarget.9069

Abstract

Inhibitor of kappa B kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IKKs. IKKε and TBK1 share the kinase domain and are similar in their ability to activate the nuclear factor-kappa B signaling pathway. IKKε and TBK1 are overexpressed through multiple mechanisms in various human cancers. However, the expression of IKKε and TBK1 in gastric cancer and their role in prognosis have not been studied.To investigate overexpression of the IKKε and TBK1 proteins in gastric cancer and their relationship with clinicopathologic factors, we performed immunohistochemical staining using a tissue microarray. Tissue microarray samples were obtained from 1,107 gastric cancer patients who underwent R0 gastrectomy with extensive lymph node dissection and adjuvant chemotherapy.We identified expression of IKKε in 150 (13.6%) and TBK1 in 38 (3.4%) gastric cancers. Furthermore, co-expression of IKKε and TBK1 was identified in 1.5% of cases. Co-expression of IKKε and TBK1 was associated with differentiated intestinal histology and earlier T stage. In a multivariate binary logistic regression model, intestinal histologic type by Lauren classification and early AJCC stage were significant predictors for expression of IKKε and TBK1 proteins in gastric cancer. Changes in IKKε and TBK1 expression may be involved in the development of intestinal-type gastric cancer. The overexpression of IKKε and TBK1 should be considered in selected patients with intestinal-type gastric cancer.In conclusion, this is the first large-scale study investigating the relationships between expression of IKKε and TBK1 and clinicopathologic features of gastric cancer. The role of IKKε and TBK1 in intestinal-type gastric cancer pathogenesis should be elucidated by further investigation.

Highlights

Gastric cancer is the third leading cause of cancerrelated death worldwide
Expression of IKKε and TANK-binding kinase 1 (TBK1) was observed in 13.6% (150/1107) and 3.4% (38/1107) of gastric cancer patients, respectively
We identified IKKε and TBK1 expression in 13.6% and 3.4% of gastric cancers, respectively, and co-expression of IKKε and TBK1 in 1.5% of cases

Summary

Introduction

Gastric cancer is the third leading cause of cancerrelated death worldwide. Identifying effective pathway inhibition is a key aspect of the development of targeted therapeutics. The success of trastuzumab in HER2-positive gastric cancer patients has elicited efforts to discover new molecular targets in gastric cancer. The nuclear factor-kappa B (NF-κB) pathway is a key regulator that activates transcription of genes involved the inflammatory immune response, proliferation, cell survival and cell invasion. NF-κB complexes are retained in the cytoplasm by a family of NF-κB-binding proteins known as inhibitors of NF-κB (IκBs) [1]. Various stimulants trigger activation of www.impactjournals.com/oncotarget the IKK (IκBs kinase complex), leading to proteasomal degradation of IκBs. NF-κB dimers are released in the nucleus and induce transcription of target genes related to inflammation and survival

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Conclusion