|Year : 2017 | Volume
| Issue : 4 | Page : 664-668
Overexpression of KIAA1199: An independent prognostic marker in nonsmall cell lung cancer
Fei Deng1, Jie Lei2, Xueqin Zhang3, Weiwei Huang4, Yongjun Li3, Dehua Wu5
1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515; Department of Oncology, The Second People's Hospital of Yichang, Three Gorges University, Yichang 443000, P. R. China
2 Department of Pathology, The Second People's Hospital of Yichang, Three Gorges University, Yichang 443000, P. R. China
3 Department of Oncology, The Second People's Hospital of Yichang, Three Gorges University, Yichang 443000, P. R. China
4 Department of Emergency, The Second People's Hospital of Yichang, Three Gorges University, Yichang 443000, P. R. China
5 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P. R. China
|Date of Web Publication||13-Sep-2017|
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, Guangzhou 510515
P. R. China
Source of Support: None, Conflict of Interest: None
Objective: KIAA1199 has been identified as an oncogene in many cancers. Here, we collected 153 cases of nonsmall cell lung cancer (NSCLC) tissues to investigate the relationships between KIAA1199 protein and clinical factors.
Materials and Methods: Immunohistochemistry (IHC) staining was used to detect the expression of KIAA1199. Follow-up included blood analysis, chest X-ray, ultrasound examination, and computed tomography was carried out every 3 months for the first 2 years and at 6-month intervals thereafter during the follow-up period (3 years). Kaplan–Meier survival analysis and Cox analysis were applied to identify the relationship between KIAA1199 and NSCLC.
Results: IHC results showed that 76 (49.67%) specimens had strong expression of KIAA1199 protein, with poor differentiation (P = 0.003), higher positive lymph node metastasis (P = 0.037), and higher tumor node metastasis stage (P = 0.016). Using Kaplan–Meier survival analysis, it is found that patients with high KIAA1199 protein expression have poor overall survival (P = 0.004). Cox analysis suggested that the KIAA1199 protein was an independent prognostic marker for NSCLC patients (P = 0.040).
Conclusion: Our findings revealed that KIAA1199 protein could be applied in predicting NSCLC patient's outcome.
Keywords: KIAA1199, nonsmall cell lung cancer, prognostic marker
|How to cite this article:|
Deng F, Lei J, Zhang X, Huang W, Li Y, Wu D. Overexpression of KIAA1199: An independent prognostic marker in nonsmall cell lung cancer. J Can Res Ther 2017;13:664-8
|How to cite this URL:|
Deng F, Lei J, Zhang X, Huang W, Li Y, Wu D. Overexpression of KIAA1199: An independent prognostic marker in nonsmall cell lung cancer. J Can Res Ther [serial online] 2017 [cited 2020 Jul 7];13:664-8. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/664/214481
| > Introduction|| |
Lung cancer is one of the most lethal human malignancies in the world. The number of new lung cancers is estimated to be 221,200 in 2015, and more than 60% of them will die. Nonsmall cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. In the past few decades, the 5-year survival rate after diagnosis of NSCLC is found to be <15%, and conventional treatments are not effective enough to improve the prognosis of the disease. The molecular carcinogenesis mechanism of NSCLC remains unclear, while it is widely accepted that the NSCLC is caused by multiple alterations of gene expression, which cause abnormal changes in signaling pathways and biological behavior. Therefore, there is a need for identifying novel molecules diagnostic and therapy of NSCLC.
KIAA1199 is mainly expressed in cochlear tissues, and the mutated form of KIAA1199 might be associated with the nonsyndromic hearing loss. Upregulation of KIAA1199 gene expression will inhibit cellular mortality, and the repression of the gene may attenuate Wnt-signaling pathway of colon cancer cells., Besides, the high expression of KIAA1199 plays an important role in tumor progression in colorectal cancer. Induction of this protein in colon cancer cells will cause a poor prognosis. Several studies have also been performed in gastric cancer, and breast cancer and conclusions were similar., However, currently, the relationship between KIAA1199 and NSCLC is still unclear.
In the present study, we compared the KIAA1199 expression in NSCLC and normal lung tissues and analyzed the clinical pathological and prognostic significance of KIAA1199 in NSCLC patients. Our aim was to confirm whether the expression of KIAA1199 can be used to predict the prognosis of NSCLC.
| > Materials and Methods|| |
Patients and specimens
A total of 153 cases of tumor specimens were collected from patients who underwent biopsy or surgical resection and were diagnosed as lung adenocarcinoma (AC) or squamous cell carcinoma (SCC) in our hospital between January 2008 and December 2013. Meanwhile, 45 normal lung tissues were taken as normal control. The pathological staging was based on the International Staging System. The informed consent was obtained from all patients, and the study was approved by the Ethics Committee of Nanfang Hospital, Southern Medical University.
One hundred and fifty-three NSCLC and 45 normal formalin-fixed paraffin-embedded tissues were used for the immunohistochemistry (IHC) studies. Briefly, the tissue was sliced continuously into about 4 μm sections, and the slides were deparaffinized and rehydrated. After blocked with 3% hydrogen peroxide in methanol, nonspecific binding was blocked with goat serum. Anti-KIAA1199 antibody (1:20, Atlas More Details) was added and incubated overnight at 4°C. The sections were then incubated with biotin-labeled secondary antibodies (1:500, Abcam) for 30 min at room temperature and horseradish peroxidase-labeled streptavidin was added. All slides were analyzed and calculated by two independent pathologists. The statistical method of final IHC score was followed by previous studies.,
Follow-up including blood analysis, chest X-ray, ultrasound examination, and computed tomography was undertaken. Each patient was scheduled for an examination every 3 months for the first 2 years and at 6-month intervals thereafter during the follow-up period (3 years).
All statistical analyses were performed by SPSS version 19.0 software (SPSS, Inc., Chicago, IL, USA). Chi-squared test was used to examine the association between KIAA1199 protein expression and patients' clinicopathologic factors. The comparison of survival time was showed by Kaplan–Meier curves, and statistical differences were compared with a log-rank test. The prognostic value was determined by multivariate Cox regression analysis. P < 0.05 was considered statistically significant.
| > Results|| |
To understand the clinical features of patients, detailed data of the patients, such as gender, age, differentiation degree, tumor node metastasis (TNM) stage, were collected from the medical records, which were summarized in supplementary data 1. Of the 153 patients in this study, 119 (77.78%) were men and 34 (22.22%) were women, ranging in age from 20 to 82 years. Lymph node metastasis was detected in 104 patients (67.97%) and the overall survival (OS) months ranged from 2 months to more than 3 years.
KIAA1199 protein expression
To identify the expression and location of KIAA1199 protein, IHC analysis was performed, and the results revealed that strong and weak/negative staining of KIAA1199 could both be detected in the normal lung, AC, and SCC tissues. The representative images were shown in [Figure 1]. In addition, we found that the staining of KIAA1199 protein was mainly located in the cell cytoplasm. In some cases, KIAA1199 protein was detected in the nucleus and cytoplasm [Figure 2].
|Figure 1: Representative images of staining of KIAA1199 in normal lung and NSCLC tissue by immunohistochemistry. (a) Weak KIAA1199 staining in normal lung tissue. (b) Strong KIAA1199 staining in normal lung tissue. (c) Weak KIAA1199 staining in squamous cell carcinoma. (d) Strong KIAA1199 staining in squamous cell carcinoma. (e) Weak KIAA1199 staining in adenocarcinoma. (f) Strong KIAA1199 staining in adenocarcinoma|
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|Figure 2: Representative images of nuclear staining of KIAA1199 in nonsmall cell lung cancer tissue by immunohistochemistry. (a) Squamous cell carcinoma. (b) Adenocarcinoma|
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In this study, 76 of 153 NSCLC tissues (49.67%) showed KIAA1199 protein overexpression, and the other 77 cases (50.23%) showed weak positive or negative of KIAA1199 protein expression. However, in normal lung tissues, 11 out of 45 normal tissues (24.44%) showed KIAA1199 protein overexpression and other 34 cases (75.56%) showed weak positive or negative KIAA1199 protein expression. Statistical analysis showed that KIAA1199 protein expression was upregulated in NSCLS tissues than normal lung tissue [Table 1], P = 0.003]. This result showed that KIAA1199 protein expression might be linked to NSCLS.
|Table 1: Expression of KIAA1199 in normal lung and nonsmall cell lung cancer tissues|
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Correlation between KIAA1199 protein and clinicopathologic factors
To investigate whether KIAA1199 protein was associated with NSCLC progression, we analyzed the correlation between KIAA1199 protein expression and clinicopathologic parameters in 153 patients with NSCLC. As shown in [Table 2], it was found that high KIAA1199 protein expression was significantly associated with poor differentiation (P = 0.003), higher TNM stage (P = 0.016), and positive lymph node metastasis (P = 0.037) but not with gender and age (P > 0.05). Besides, high KIAA1199 protein expression was more common in AC than SCC (P = 0.001). The result suggested that KIAA1199 protein expression was associated with clinicopathologic parameters such as poor differentiation, higher TNM stage, and positive lymph node metastasis.
|Table 2: Correlation between clinicopathological parameters and KIAA1199 protein expression|
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Univariate and multivariate survival analyses
To investigate the effect of KIAA1199 protein on NSCLC prognosis, survival analysis on these 153 patients was performed. First, the association between clinicopathologic factors and patients' outcomes was analyzed. It was shown that poor histopathologic differentiation (23.69 ± 1.27 vs. 15.36 ± 1.33, P < 0.05), positive lymph node metastasis (15.88 ± 1.10 vs. 27.33 ± 1.43, P < 0.05), and high TNM stage (28.22 ± 1.28 vs. 15.34 ± 1.09, P < 0.05) were associated with a significantly worse OS [Table 3]. Then, we analyzed the prognostic significance of KIAA1199 protein. Kaplan–Meier analysis of OS showed that patients with KIAA1199 protein overexpression (16.01 ± 1.38 vs. 23.04 ± 1.26, P < 0.05) [Table 3] had a poor 3-year survival rate [Figure 3]. A multivariate Cox regression model was used to analyze the independent factors of NSCLC prognosis. It was shown that KIAA1199 protein expression (relative risk: 0.711 [0.512–0.985], P < 0.05) and TNM stage (relative risk: 0.591 [0.392–0.890], P < 0.05) were independent prognostic factors of patients' OS [Table 4]. This result indicated that KIAA1199 protein expression might be used as an independent prognostic marker in NSCLC.
|Table 3: Univariate Kaplan-Meier survival analysis of overall survival in 153 patients with nonsmall cell lung cancer|
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|Figure 3: Kaplan–Meier curves of overall survival according to the level of KIAA1199 protein expression|
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|Table 4: Multivariate Cox regression model of overall survival in 153 patients with nonsmall cell lung cancer|
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| > Discussion|| |
NSCLC is characterized by the presence of highly malignant, poor prognosis, and short-term survival. Numerous studies and clinical trials have tried to elucidate the factors that influence tumor progression, but few advances have been made in the past 15 years. Genetic abnormalities have been taken into account in the recurrence and early metastasis of NSCLC.,, Therefore, it is important to explore new prognostic markers to predict unfavorable prognosis in patients with NSCLC.
KIAA1199 is a glycosylated protein, located in the cytoplasm and membrane, especially the endoplasmic reticulum.,, Many studies have focused on the relationship between cancer and KIAA1199. In breast tumor, KIAA1199 can regulate cell growth and invasiveness and could be a novel therapeutic target. The similar analysis reported that KIAA1199 overexpression predicts poor survival in patients with colon cancer. KIAA1199 protein can promote tumor progression by several mechanisms. Other studies have shown that the protein expression level was elevated upon p53 activation. The expression of KIAA1199 was also induced in hypoxia and was regulated by JARID1A, resulting in cell migration. Furthermore, the activation of nuclear factor-κB pathway could induce KIAA1199 and then transmit pro-survival and invasive signals. KIAA1199 was also associated with angiogenesis in rheumatoid arthritis. However, little is known about the mechanism of KIAA1199 tumor-promoting effects in NSCLC.
In this study, we detected the expression of KIAA1199 protein and then analyzed the prognostic value of KIAA1199 protein in patients with NSCLC. Our results demonstrated the significant associations of KIAA1199 protein with prognosis-related features including histopathologic differentiation, TNM stage, and lymph node metastasis. It was likely that KIAA1199 protein played an important role in NSCLC progression. Further statistical analysis revealed that the OS time of patients with high KIAA1199 protein expression was worse than those with low KIAA1199 protein expression, indicating that KIAA1199 protein overexpression was significantly related with poor 3-year survival rate. Histopathologic differentiation, TNM stage, and lymph node metastasis were also involved in patient survival. Multivariate survival analysis manifested that KIAA1199 and TNM stage were significant independent prognostic factors for OS of NSCLC patients. Based on these observations, we hypothesized that KIAA1199 could regulate NSCLC progression. We also found that four cases of KIAA1199 were detected in the nucleus. Translocation of protein may be involved in transcription regulation such as beta-catenin. However, the number of samples was so small that statistical analysis could not be performed. In the future, we need to investigate whether this translocation of KIAA1199 protein predicts a poor prognosis with more patients' data.
| > Conclusion|| |
Our results revealed the significant associations of KIAA1199 protein expression with various clinicopathologic characteristics and prognostic in patients with NSCLC. Moreover, survival analysis showed that KIAA1199 was an independent prognostic factor for OS in NSCLC. All of these findings indicated that KIAA1199 protein might be used as a pathological marker to identify individuals with poor outcomes and to provide a reference for clinical therapy in the future.
Financial support and sponsorship
This study was funded by Medical and Health Research Projects of Yichang (A14301-30).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME. The international epidemiology of lung cancer: Latest trends, disparities, and tumor characteristics. J Thorac Oncol 2016;11:1653-71.
Youlden DR, Cramb SM, Baade PD. The international epidemiology of lung cancer: Geographical distribution and secular trends. J Thorac Oncol 2008;3:819-31.
Abe S, Usami S, Nakamura Y. Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss. J Hum Genet 2003;48:564-70.
Michishita E, Garcés G, Barrett JC, Horikawa I. Upregulation of the KIAA1199 gene is associated with cellular mortality. Cancer Lett 2006;239:71-7.
Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, Thorsen K, Andersen CL, Øster B, et al.
Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells. Br J Cancer 2011;105:552-61.
Xu J, Liu Y, Wang X, Huang J, Zhu H, Hu Z, et al.
Association between KIAA1199 overexpression and tumor invasion, TNM stage, and poor prognosis in colorectal cancer. Int J Clin Exp Pathol 2015;8:2909-18.
Fink SP, Myeroff LL, Kariv R, Platzer P, Xin B, Mikkola D, et al.
Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival. Oncotarget 2015;6:30500-15.
Jami MS, Hou J, Liu M, Varney ML, Hassan H, Dong J, et al.
Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness. BMC Cancer 2014;14:194.
Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M. Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann Surg Oncol 2009;16:2042-51.
Wittekind C. 2010 TNM system: On the 7th
edition of TNM classification of malignant tumors. Pathologe 2010;31:331-2.
Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 1987;8:138-40.
Gou HF, Chen XC, Zhu J, Jiang M, Yang Y, Cao D, et al.
Expressions of COX-2 and VEGF-C in gastric cancer: Correlations with lymphangiogenesis and prognostic implications. J Exp Clin Cancer Res 2011;30:14.
Coate LE, John T, Tsao MS, Shepherd FA. Molecular predictive and prognostic markers in non-small-cell lung cancer. Lancet Oncol 2009;10:1001-10.
Mohammed AA, El-Tanni H, Alsakkaf MA, Mirza AA, Atiah TA, Atiah AA. Genomic aberrations in non- small cell lung cancer and their impact on treatment outcome. J Cancer Res Ther 2017;13:9-15.
Zhang K, Zhang M, Zhu J, Hong W. Screening of gene mutations associated with bone metastasis in nonsmall cell lung cancer. J Cancer Res Ther 2016;12:C186-90.
Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski MJ, Roschitzki B, et al.
Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors. PLoS One 2013;8:e69473.
Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Kadam P, et al.
Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst 2013;105:1402-16.
Shostak K, Zhang X, Hubert P, Göktuna SI, Jiang Z, Klevernic I, et al.
NF-κB-induced KIAA1199 promotes survival through EGFR signalling. Nat Commun 2014;5:5232.
Yang X, Qiu P, Chen B, Lin Y, Zhou Z, Ge R, et al.
KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. Arthritis Res Ther 2015;17:140.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]