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Expression and Prognostic Role of IKBKE and TBK1 in Stage I Non-Small Cell Lung Cancer

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Expression and Prognostic Role of IKBKE and TBK1 in Stage I Non-Small Cell Lung Cancer Cancer Management and Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Expression and prognostic role of IKBKE and TBK1 in stage I non-small cell lung cancer This article was published in the following Dove Press journal: Cancer Management and Research Xin Wang1,2 Background: The inhibitors of nuclear factor kappa-B kinase subunit epsilon (IKBKE) and Feifei Teng2 TANK-binding kinase 1 (TBK1) are important members of the nonclassical IKK family that Jie Lu3 share the kinase domain. They are important oncogenes for activation of several signaling Dianbin Mu4 pathways in several tumors. This study aims to explore the expression of IKBKE and TBK1 Jianbo Zhang4 and their prognostic role in stage I non-small cell lung cancer (NSCLC). Jinming Yu1,2 Patients and methods: A total of 142 surgically resected stage I NSCLC patients were enrolled and immunohistochemistry of IKBKE and TBK1 was performed. 1 Department of Oncology, Renmin Results: IKBKE and TBK1 were expressed in 121 (85.2%) and 114 (80.3%) of stage I Hospital of Wuhan University, Wuhan, fi Hubei 430060, People’s Republic of China; NSCLC patients respectively. IKBKE expression was signi cantly associated with TBK1 2Department of Radiation Oncology, expression (P=0.004). Furthermore, multivariate regression analyses showed there was a fi Shandong Cancer Hospital Af liated to significant relationship between patients with risk factors, the recurrence pattern of metas- Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong tasis and IKBKE+/TBK1+ co-expression (P=0.032 and P=0.022, respectively). In Kaplan– 250117, People’s Republic of China; Meier survival curve analyses, the IKBKE+/TBK1+ co-expression subgroup was signifi- 3Department of Neurosurgery, Shandong Province Qianfoshan Hospital of Shandong cantly associated with poor overall survival (P=0.014). University, Jinan, Shandong 250014, Conclusions: This is the first study to investigate the relationship between IKBKE and 4 People’s Republic of China; Department TBK1 expression and clinicopathologic characteristics in stage I NSCLC patients. IKBKE of Pathology, Shandong Cancer Hospital fi Affiliated to Shandong University, +/TBK1+ co-expression was signi cantly obvious in patients with risk factors and with Shandong Academy of Medical Sciences, recurrence pattern of distant metastasis. Furthermore, IKBKE+/TBK1+ is also an effective ’ Jinan, Shandong 250117, People sRepublic prognostic predictor for poor overall survival. of China Keywords: IKBKE, TBK1, NSCLC, prognosis, cancer Introduction Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer(NSCLC) accounts for 80–85% of all lung cancer cases.1,2 The primary treatment for stage I NSCLC is surgical resection, but at least 30% of patients experienced recurrence within 5 years.3 Adjuvant chemotherapy is recommended for patients with risk factors, such as poor histologic differentiation, vascular invasion, wedge resection, tumors >4 cm, incomplete lymph node sampling, and visceral pleural invasion.4 Even after receiving adjuvant chemotherapy, the 5-year survival rate is only 60–90% due to local recurrence or distant metastasis.5,6 Therefore, we defined high-risk patients as tending to local recurrence or distant metastasis. It is challenging to screen true high-risk patients for adjuvant che- Correspondence: Jinming Yu motherapy, and to avoid unnecessary adjuvant chemotherapy in low-risk patients Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, to reduce the survival reduction caused by treatment-related toxicity. Hubei 430060, People’s Republic of China The IKK family contains five protein factors. IKKα, IKKβ, and IKKγ belong to Tel +86 6762 6971 Email [email protected] canonical group, and the other two (IKBKE and TBK1) belong to non-canonical submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 6593–6602 6593 DovePress © 2019 Wang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the http://doi.org/10.2147/CMAR.S204924 work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Wang et al Dovepress group.7 The amino acid sequence analysis confirmed that in room temperature (RT). Then, all sections were incubated IKBKE has 67% homology with TBK1.8 IKBKE is highly at 4°C overnight with primary anti-IKBKE (ab7891, Abcam, expressed in human normal pancreatic tissue, thyroid tis- IHC 1:100, Cambridge, MA) or anti-TBK1 (ab109735, sue, spleen, and peripheral blood leukocytes, and can be Abcam, IHC 1:400, Cambridge, MA). Then, the specimens up-regulated by multiple cytokines such as tumor necrosis were incubated with biotinylated secondary antibodies for 1 factor alpha (TNF-α), IL-1, IL-6, and interferon-γ.9 TBK1 hr in RT. After incubation with ABC-peroxidase for 1 hr then is constitutively expressed in immune cells, brain, lungs, all sections were colored using a DAB Kit (ZSGB-BIO, gastrointestinal tract, and reproductive organs.10 Studies People’s Republic of China) and counterstained with hema- have demonstrated that IKBEK and TBK1 need to bind toxylin. All IHC results were evaluated by two pathologists. to scaffold proteins to form a protease complex to activate Double-blind readings were performed by two pathologists downstream protein factors, thereby activating the NF-κB at the unknown tumor grade, and 10 fields were randomly pathway. TNAK (TNF receptor-associated factor family collected from each pathological section, and the percentage member-associated NF-κB activator), NAP1 (NAK asso- of positive cells and the intensity of staining were scored: 1) ciated protein 1), and SINTBAD (similar to NAP and coloring cells accounted for <5% cell count is 0; 5–25% is 1 TBK1 adaptor) are the main scaffold proteins.11–17 point; 26–50% is 2 points; 51–75% is 3 points; and >75% is 4 Several studies have shown that IKBKE was overex- points; 2) no staining is 0 points; the light yellow is 1 point; pressed in breast cancer, glioma, gastric cancer, pancreatic the brown and yellow is 2 points; the sepia is 3 points; 3) the cancer, ovarian cancer, renal cancer, and lung cancer and two points are multiplied to form a positive grade: 0 is was associated with poor prognosis.18–24 IKBKE and negative (-), 1–4isweaklypositive(+),5–8 is positive (+ TBK1 may play important roles in tumorigenesis, prolif- +), and 9–12 is strongly positive (+++). eration, and angiogenesis.25,26 Nevertheless, the associa- tion between IKBKE and TBK1 expression and Statistical analysis clinicopathological characteristics and its role in the prog- The categorical variables were tested using Pearson’schi- nosis of stage I NSCLC has not been reported. squared tests or Fisher’s exact test, and continuous variables were expressed as means±SD and were analyzed using inde- Patients and methods pendent t-test. The significant (P<0.05) clinicopathological Patient selection characteristics in univariate analysis were enrolled in multi- A totlal of 142 tissue samples were retrospectively col- variate logistic regression analysis, and multivariate logistic fi lected from patients who were pathologically diagnosed regression analysis was used to con rm the independent with stage I NSCLC between January 2004 and June 2012 clinicopathological characteristics which were associated – in Shandong Cancer hospital. All of them received anato- with IKBKE and TBK1 expression. The Kaplan Meier was mical segmentectomy or standard lobectomy via open used to analyze progression-free survival (PFS) and OS, and thoracotomy and did not receive other treatments except the survival curves of four subgroups were compared by log- for surgery. This retrospective study was approved by the rank test. All analysis was two-sided, and P<0.05 was con- fi ethics committee at Shandong Cancer Hospital and sidered statistically signi cant. Statistical analysis was per- Institute. All patients have provided written informed con- formed using SPSS (version 20.0). sent, and this study was conducted in accordance with the Declaration of Helsinki. Results Expression of IKBKE and TBK1 and their Immunohistochemistry association in stage I NSCLC patients Tumor tissue samples were obtained from 142 surgically Among the 142 enrolled stage I NSCLC patients, 48 resected stage I NSCLC patients. Surgically resected speci- (33.8%) patients were squamous cell carcinoma, and 65 mens were fixed in formalin and embedded in paraffin. Then, patients (45.8%) were adenocarcinoma. Twenty-nine 4-μmparaffin-embedded sections were dewaxed and heated patients were other types of NSCLC including 8 large to 95°C for 20 mins for antigen retrieval in 10 mmol/L citrate cell carcinoma, 5 atypical carcinoid tumor, 5 pleomorphic buffer. Then, the sections were cleared of endogenous per- carcinoma, 9 adenosquamous carcinoma, and 2 mucinous oxidase activity and were blocked with 5% BSA for 30 mins epidermoid carcinoma. IKBKE and TBK1 expression was 6594 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 DovePress Dovepress Wang et al found in 85.2% (n=121) and 80.3% (n=114) of stage I OR of patients with recurrence pattern of metastasis was NSCLC patients, respectively. The association between 1.670, with a 95% CI 1.078–2.587 when compared with IKBKE and TBK1 expression and clinicopathological patients with recurrence pattern of local recurrence characteristics is summarized in Table 1. IKBKE and (Table 4). TBK1 expression was associated with risk factors (P=0.021 and P=0.014). From Table 1 we found patients The prognostic significance of IKBKE and with risk factors showed increased IKBKE and TBK1 TBK1 co-expression in stage I NSCLC expression compared to patients who had no risk factors.
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