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Prognostic significance of CD276 in non-small cell lung cancer

  • Changgong Zhang and Xuezhi Hao EMAIL logo
Published/Copyright: November 7, 2019
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Open Medicine
From the journal Open Medicine Volume 14 Issue 1

Abstract

Background

The expression and significance of CD276 in non-small cell lung cancer (NSCLC) was explored.

Method

The BioGPS database was used to analyze the expression level of CD276 in normal tissues. Studies on the expression of CD276 in NSCLC patients using the Oncomine database. The prognostic roles of CD276 in NSCLC was studied using the Kaplan-Meier plotter database.

Result

The BioGPS database showed CD276 expression in all the human normal tissues. Compared with normal lung tissue, CD276 gene highly expressed in NSCLC tissue at mRNA level (P<0.05). The expression level of CD276 gene was negatively correlated with overall survival (OS) of NSCLC patients. Subgroup analysis showed that CD276 expression level had a significant effect on OS of patients with lung adenocarcinoma, while in squamous cell carcinoma its expression level had no significant effect on OS.

Conclusion

According to the information mined from the tumor gene database, CD276 mRNA was found highly expressed in NSCLC tissue and the expression of CD276 has a significant impact on survival of NSCLC patients, which provides an important theoretical basis for further study of the role of CD276 in the occurrence and development of NSCLC.

Keywords: Non-small cell lung cancer; CD276; Oncomine; Prognosis

1 Introduction

Lung cancer has become the leading cause of cancer-related deaths worldwide. Its incidence and mortality are increasing year by year [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancer patients, and more than half of NSCLC patients are locally advanced or distantly metastatic at the time of diagnosis [2]. Therefore, improving the early diagnosis rate of NSCLC, discovering new indicators for evaluating prognosis, and new targets for anti-tumor therapy have become the focus of current NSCLC research.

CD276 is a type I transmembrane protein and its extracellular domain consists of two immunoglobulin constant (IgC) and variable (IgV) domains [3]. CD276 is a co-stimulatory/co-inhibitory molecule. When Chapoval et al first reported CD276, it was found to have a co-stimulatory effect on CD4 + and CD8 + cells. As a co-stimulatory molecule, CD276 signal induces cellular immunity. CD276 enhances the induction of cytotoxic T cells and selectively stimulates interferon gamma production (IFNγ) [4]. However, with the deepening of research, experiments have shown that the co-inhibition of CD276 in humans and mice can inhibit Treg cells [5], thereby allowing tumors to escape immune responses, and the mechanism may be related to NFAT, NF-kB and AP-1 factors [6]. Taken together, these results suggest that the immune function of CD276 remains controversial, with conflicting co-stimulatory and co-suppressive functions, which may be associated with CD276 and multiple possible associated molecular expressions, such as programmed death receptor 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), or related to the presence of different types of immune response-related cells.

There are few studies on whether CD276 plays a role in NSCLC and its function in the development of NSCLC. This study used a database to analyze the expression of CD276 gene in NSCLC and its impact on prognosis.

2 Materials and methods

2.1 The BioGPS database

Analysis of CD276 expression in normal human tissues was made using BioGPS database [7].

2.2 The Oncomine database

Oncomine database is currently the largest number of oncogene arrays integrated data mining platform in the world [8]. In this database, the conditions for filtering and data mining can be set. The screening conditions set in this study are: “Gene: CD276”; “Analysis Type: Lung Cancer vs. Normal Analysis”; “Cancer Type: Lung Cancer”; “Sample Type: Clinical Specimen”; “Data Type: mRNA”.

2.3 The Kaplan-Meier Plotter

Online survival analysis was performed using the lung cancer dataset of the Kaplan-Meier Plotter (KM Plotter) [9]. The screening conditions are as follows: “Cancer: Lung Cancer”; “Gene: CD276”; “Survival: OS”.

2.4 The String database explores protein-protein interactions

The database is a search tool for analyzing biological gene or protein interactions, including biological databases and network resources for proven and predictable protein-protein interactions [10]. In this study, the search term used was “CD276”, with the species type as “Homo sapiens”, the confidence level at “Medium 0.400”, and the maximum number of interactions as 10.

2.5 Statistical processing

The difference in CD276 gene expression between NSCLC and normal lung tissue was analyzed by t test. The relationship between CD276 gene expression and prognosis was analyzed by Kaplan-Meier model. The survival rate between the two groups was compared by Log-Rank test. The test level was α=0.05. The data used were analyzed by online statistical analysis. P<0.05 was considered statistically significant.

3 Results

3.1 Expression of CD276 in normal human tissues

The BioGPS database showed that the CD276 gene was expressed in all normal tissues of the human body, with higher levels in bronchial epithelial cells and the uterus (Figure 1).

Figure 1 Expression of CD276 in normal human tissues
Figure 1

Expression of CD276 in normal human tissues

3.2 Expression of CD276 in common tumor types

A total of 436 different types of microarray studies were collected in the Oncomine database, and 29 of them had statistically significant differences in CD276 expression, including 22 studies of increased CD276 expression and three studies of decreased CD276 expression (Figure 2).

Figure 2 Expression of CD276 in common tumor types
Figure 2

Expression of CD276 in common tumor types

3.3 Expression of CD276 in NSCLC

A search in the Oncomine database found that 6 studies had focused on the expression of CD276 in NSCLC and normal lung tissue since 2003, including a total of 591 samples (Figure 3). The article was published in Proc Natl Acad Sci [11], PLoS One [12], Cancer Res [13], Genome Res [14]. A meta-analysis of the results of these 6 studies revealed that CD276 was highly expressed in NSCLC tissues compared with normal lung tissues, with a median rank of 3176 and P=0.004, indicating statistical significance.

Figure 3 Differential expression of CD276 in NSCLC and normal lung tissues
Figure 3

Differential expression of CD276 in NSCLC and normal lung tissues

3.4 Differential expression of CD276 in NSCLC and normal lung tissues

Data mining of Oncomine showed that CD276 was highly expressed in different types of NSCLC research arrays compared with normal lung tissue, and the difference was statistically significant (Figure 4). In the study by Garber et al, CD276 mRNA expression was 1.675 times higher in lung adenocarcinoma (40 cases) than normal lung tissue (5 cases) (P = 0.007, Figure 4A). In the study by Selamat et al, the expression of CD276 mRNA was increased by 1.613 times in lung adenocarcinoma (58 cases) compared with normal lung tissue (58 cases) (P = 8.55E-14, Figure 4B). In Okayama et al, the expression of CD276 mRNA was 1.443 times higher in lung adenocarcinoma (226 cases) than in normal lung tissues (20 cases) (P = 7.10E-5, Figure 4C). In

Figure 4 Differential expression of CD276 in NSCLC and normal lung tissues
Figure 4

Differential expression of CD276 in NSCLC and normal lung tissues

Hou et al, the expression of CD276 mRNA was 1.13 times higher in lung adenocarcinoma (45 cases) than in normal lung tissues (65 cases) (P = 6.14E-4, Figure 4D).

3.5 Relationship between CD276 expression level and prognosis of patients with NSCLC

To further clarify the relationship between CD276 expression level and the prognosis of patients with NSCLC, KM Plotter database analysis showed a survival curve of 1145 patients with high CD276 expression and low expression group, and found that CD276 expression level has a significant impact on overall survival of patients. Compared with 589 patients with low-expression NSCLC, 556 patients with high CD276 expression had significantly lower OS (HR=1.56, logrank P=1.4e-07, Figure 5A). This indicates that CD276 expression is a risk factor for prognosis in patients with NSCLC. Further subgroup analysis showed that in 673 patients with lung adenocarcinoma, high RPA3 expression levels had a significant effect on OS (HR=2.38, logrankP=3.3e-12, Figure 5B), whereas in 271 patients with lung squamous cell carcinoma, Its high expression level had no significant effect on OS (HR=0.73, logrankP=0.052, Figure 5C).

Figure 5 Relationship between CD276 expression level and prognosis of patients with NSCLC
Figure 5

Relationship between CD276 expression level and prognosis of patients with NSCLC

3.6 Protein network interacting with CD276

The protein network interacting with CD276 was obtained by String database analysis and the number of nodes was 11 (Figure. 6). Among them, CTLA4, IL2, IL4 interacted with CD276 in the PPI network (score > 0.900), and the main biological processes involved were regulation of immunoglobulin production, regulation of cytokine production and regulation of lymphocyte proliferation.

Figure 6 Protein network interacting with CD276
Figure 6

Protein network interacting with CD276

4 Discussion

At present, the incidence and mortality of lung cancer in the world are the highest among all tumors. In recent years, the application of chemotherapy, radiotherapy, targeted drugs and immunotherapy in lung cancer has significantly improved the 5-year survival rate of NSCLC [15]. Due to the problems of radiochemotherapy resistance, treatment failure, tumor recurrence and metastasis, the long-term prognosis is still very poor, and new research is urgently needed to find effective diagnostic methods and therapeutic targets.

Studies have found that CD276 is expressed at both transcriptional and translational levels in six different non-small cell lung cancer cell lines [15]. Studies have shown that CD276 helps to suppress normal immune responses and can cause cancer progression in patients with NSCLC. In histological examinations of patients with NSCLC, CD276 expression was significantly associated with NSCLC lymph node metastasis and advanced TNM stage, and CD276 was found to have an inhibitory effect on the immune system of NSCLC [16]. Another study analyzed tissue samples from 105 patients with NSCLC, not only found that high expression of CD276 protein is associated with poor prognosis, but also that CD276 can participate in the progression of NSCLC by inducing monocytes to develop into anti-inflammatory cells [17]. In another study, high CD276 expression was observed to be associated with high tumor grade and short overall survival, possibly in synergy with Treg cells, allowing tumors to evade immune responses. However, there are also statistics showing that abnormal expression of CD276 is associated with lymph node metastasis and late stage of NSCLC in TNM stage. However, there is no significant association between CD276 and overall survival in NSCLC [18, 19].

The BioGPS database is an online gene annotation database that contains information on public resources and data generated by Novartis Research [20]. The results based on BioGPS database mining showed that CD276 gene was expressed in all normal tissues of the human body, especially in bronchial epithelial cells. The Oncomine database integrates RNA-seq and DNA-seq data from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), and published literature to analyze differential expression in cancer and normal tissues [21]. This study used the Oncomine database to conduct a meta-analysis of lung cancer-related studies. The results showed that CD276 was highly expressed in NSCLC tissues in 591 specimens from 6 studies. The KM Plotter database is the world’s most widely accepted prognostic-related online analysis database, containing mRNA profiles of five cancers (breast, ovarian, lung, stomach, liver cancer), which can be used for relevant prognostic analysis of 54675 genes [22]. This study was the first to analyze the prognostic relationship between CD276 and NSCLC through the KM plotter data platform. The results showed that the expression level of CD276 was correlated with the OS of NSCLC, and the OS of patients with high CD276 expression was significantly decreased, indicating that high expression of CD276 is an independent risk factor for poor prognosis in patients with NSCLC. Subgroup analysis showed that the expression level of CD276 had a significant effect on the prognosis of patients with lung adenocarcinoma, while in patients with squamous cell carcinoma, the expression level had no significant effect on the prognosis. At present, the specific role of CD276 in the development of NSCLC and its molecular mechanism have not been studied.

In summary, through the deep mining of NSCLC-related gene information in the database, it was found that CD276 is highly expressed in NSCLC tissues and is associated with the prognosis of NSCLC. The results of these researches provide clues and evidence for further experimental research, and provide theoretical support for further research on molecular mechanisms.

  1. Conflicts of interest

    The authors have no conflicts of interest to declare.

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Received: 2019-06-04
Accepted: 2019-07-07
Published Online: 2019-11-07

© 2019 Changgong Zhang, Xuezhi Hao, published by De Gruyter

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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https://doi.org/10.1515/med-2019-0076
Keywords for this article
Non-small cell lung cancer; CD276; Oncomine; Prognosis
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  29. A spinal subdural hematoma induced by guidewire-based lumbar drainage in a patient with ruptured intracranial aneurysms
  30. Research Article
  31. High expression B3GAT3 is related with poor prognosis of liver cancer
  32. Effects of light touch on balance in patients with stroke
  33. Oncoprotein LAMTOR5 activates GLUT1 via upregulating NF-κB in liver cancer
  34. Effects of budesonide combined with noninvasive ventilation on PCT, sTREM-1, chest lung compliance, humoral immune function and quality of life in patients with AECOPD complicated with type II respiratory failure
  35. Prognostic significance of lymph node ratio in ovarian cancer
  36. Case Report
  37. Brainstem anaesthesia after retrobulbar block
  38. Review Article
  39. Treating infertility: current affairs of cross-border reproductive care
  40. Research Article
  41. Serum inflammatory cytokines comparison in gastric cancer therapy
  42. Behavioural and psychological symptoms in neurocognitive disorders: Specific patterns in dementia subtypes
  43. MRI and bone scintigraphy for breast cancer bone metastase: a meta-analysis
  44. Comparative study of back propagation artificial neural networks and logistic regression model in predicting poor prognosis after acute ischemic stroke
  45. Analysis of the factors affecting the prognosis of glioma patients
  46. Compare fuhrman nuclear and chromophobe tumor grade on chromophobe RCC
  47. Case Report
  48. Signet ring B cell lymphoma: A potential diagnostic pitfall
  49. Research Article
  50. Subparaneural injection in popliteal sciatic nerve blocks evaluated by MRI
  51. Loneliness in the context of quality of life of nursing home residents
  52. Biological characteristics of cervical precancerous cell proliferation
  53. Effects of Rehabilitation in Bankart Lesion in Non-athletes: A report of three cases
  54. Management of complications of first instance of hepatic trauma in a liver surgery unit: Portal vein ligation as a conservative therapeutic strategy
  55. Matrix metalloproteinase 2 knockdown suppresses the proliferation of HepG2 and Huh7 cells and enhances the cisplatin effect
  56. Comparison of laparoscopy and open radical nephrectomy of renal cell cancer
  57. Case Report
  58. A severe complication of myocardial dysfunction post radiofrequency ablation treatment of huge hepatic hemangioma: a case report and literature review
  59. Solar urticaria, a disease with many dark sides: is omalizumab the right therapeutic response? Reflections from a clinical case report
  60. Research Article
  61. Binge eating disorder and related features in bariatric surgery candidates
  62. Propofol versus 4-hydroxybutyric acid in pediatric cardiac catheterizations
  63. Nasointestinal tube in mechanical ventilation patients is more advantageous
  64. The change of endotracheal tube cuff pressure during laparoscopic surgery
  65. Correlation between iPTH levels on the first postoperative day after total thyroidectomy and permanent hypoparathyroidism: our experience
  66. Case Report
  67. Primary angiosarcoma of the kidney: case report and comprehensive literature review
  68. Research Article
  69. miR-107 enhances the sensitivity of breast cancer cells to paclitaxel
  70. Incidental findings in dental radiology are concerning for family doctors
  71. Suffering from cerebral small vessel disease with and without metabolic syndrome
  72. A meta-analysis of robot assisted laparoscopic radical prostatectomy versus laparoscopic radical prostatectomy
  73. Indications and outcomes of splenectomy for hematological disorders
  74. Expression of CENPE and its prognostic role in non-small cell lung cancer
  75. Barbed suture and gastrointestinal surgery. A retrospective analysis
  76. Using post transplant 1 week Tc-99m DTPA renal scan as another method for predicting renal graft failure
  77. The pseudogene PTTG3P promotes cell migration and invasion in esophageal squamous cell carcinoma
  78. Lymph node ratio versus TNM system as prognostic factor in colorectal cancer staging. A single Center experience
  79. Review Article
  80. Minimally invasive pilonidal sinus treatment: A narrative review
  81. Research Article
  82. Anatomical workspace study of Endonasal Endoscopic Transsphenoidal Approach
  83. Hounsfield Units on Lumbar Computed Tomography for Predicting Regional Bone Mineral Density
  84. Communication
  85. Aspirin, a potential GLUT1 inhibitor in a vascular endothelial cell line
  86. Research Article
  87. Osteopontin and fatty acid binding protein in ifosfamide-treated rats
  88. Familial polyposis coli: the management of desmoid tumor bleeding
  89. microRNA-27a-3p down-regulation inhibits malignant biological behaviors of ovarian cancer by targeting BTG1
  90. PYCR1 is associated with papillary renal cell carcinoma progression
  91. Prediction of recurrence-associated death from localized prostate cancer with a charlson comorbidity index–reinforced machine learning model
  92. Colorectal cancer in the elderly patient: the role of neo-adjuvant therapy
  93. Association between MTHFR genetic polymorphism and Parkinson’s disease susceptibility: a meta-analysis
  94. Metformin can alleviate the symptom of patient with diabetic nephropathy through reducing the serum level of Hcy and IL-33
  95. Case Report
  96. Severe craniofacial trauma after multiple pistol shots
  97. Research Article
  98. Echocardiography evaluation of left ventricular diastolic function in elderly women with metabolic syndrome
  99. Tailored surgery in inguinal hernia repair. The role of subarachnoid anesthesia: a retrospective study
  100. The factors affecting early death in newly diagnosed APL patients
  101. Review Article
  102. Oncological outcomes and quality of life after rectal cancer surgery
  103. Research Article
  104. MiR-638 repressed vascular smooth muscle cell glycolysis by targeting LDHA
  105. microRNA-16 via Twist1 inhibits EMT induced by PM2.5 exposure in human hepatocellular carcinoma
  106. Analyzing the semantic space of the Hippocratic Oath
  107. Fournier’s gangrene and intravenous drug abuse: an unusual case report and review of the literature
  108. Evaluation of surgical site infection in mini-invasive urological surgery
  109. Dihydromyricetin attenuates inflammation through TLR4/NF-kappaB pathway
  110. Clinico-pathological features of colon cancer patients undergoing emergency surgery: a comparison between elderly and non-elderly patients
  111. Case Report
  112. Appendix bleeding with painless bloody diarrhea: A case report and literature review
  113. Research Article
  114. Protective effects of specneuzhenide on renal injury in rats with diabetic nephropathy
  115. PBF, a proto-oncogene in esophageal carcinoma
  116. Use of rituximab in NHL malt type pregnant in I° trimester for two times
  117. Cancer- and non-cancer related chronic pain: from the physiopathological basics to management
  118. Case report
  119. Non-surgical removal of dens invaginatus in maxillary lateral incisor using CBCT: Two-year follow-up case report
  120. Research Article
  121. Risk factors and drug resistance of the MDR Acinetobacter baumannii in pneumonia patients in ICU
  122. Accuracy of tumor perfusion assessment in Rat C6 gliomas model with USPIO
  123. Lemann Index for Assessment of Crohn’s Disease: Correlation with the Quality of Life, Endoscopic Disease activity, Magnetic Resonance Index of Activity and C- Reactive Protein
  124. Case report
  125. Münchausen syndrome as an unusual cause of pseudo-resistant hypertension: a case report
  126. Research Article
  127. Renal artery embolization before radical nephrectomy for complex renal tumour: which are the true advantages?
  128. Prognostic significance of CD276 in non-small cell lung cancer
  129. Potential drug-drug interactions in acute ischemic stroke patients at the Neurological Intensive Care Unit
  130. Effect of vitamin D3 on lung damage induced by cigarette smoke in mice
  131. CircRNA-UCK2 increased TET1 inhibits proliferation and invasion of prostate cancer cells via sponge miRNA-767-5p
  132. Case report
  133. Partial hydatidiform mole and coexistent live fetus: a case report and review of the literature
  134. Research Article
  135. Effect of NGR1 on the atopic dermatitis model and its mechanisms
  136. Clinical features of infertile men carrying a chromosome 9 translocation
  137. Review Article
  138. Expression and role of microRNA-663b in childhood acute lymphocytic leukemia and its mechanism
  139. Case Report
  140. Mature cystic teratoma of the pancreas: A rare cystic neoplasm
  141. Research Article
  142. Application of exercised-based pre-rehabilitation in perioperative period of patients with gastric cancer
  143. Case Report
  144. Predictive factors of intestinal necrosis in acute mesenteric ischemia
  145. Research Article
  146. Application of exercised-based pre-rehabilitation in perioperative period of patients with gastric cancer
  147. Effects of dexmedetomidine on the RhoA /ROCK/ Nox4 signaling pathway in renal fibrosis of diabetic rats
  148. MicroRNA-181a-5p regulates inflammatory response of macrophages in sepsis
  149. Intraventricular pressure in non-communicating hydrocephalus patients before endoscopic third ventriculostomy
  150. CyclinD1 is a new target gene of tumor suppressor miR-520e in breast cancer
  151. CHL1 and NrCAM are primarily expressed in low grade pediatric neuroblastoma
  152. Epidemiological characteristics of postoperative sepsis
  153. Association between unstable angina and CXCL17: a new potential biomarker
  154. Cardiac strains as a tool for optimization of cardiac resynchronization therapy in non-responders: a pilot study
  155. Case Report
  156. Resuscitation following a bupivacaine injection for a cervical paravertebral block
  157. Research Article
  158. CGF treatment of leg ulcers: A randomized controlled trial
  159. Surgical versus sequential hybrid treatment of carotid body tumors
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