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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 914-920

mRNA expression of programmed cell death ligand 1 and components of the phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway in epidermal growth factor receptor mutation-positive lung adenocarcinoma


Department of Thoracic Surgery, Xuan Wu Hospital of Capital Medical University, Beijing 100053, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Yi Zhang
Department of Thoracic Surgery, Xuan Wu Hospital of Capital Medical University, Beijing 100053
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_636_18

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 > Abstract 


Objective: The objective of this study is to investigate the relationship between programmed cell death ligand 1 (PD-L1) expression and the mutation status of epidermal growth factor receptor (EGFR) in lung adenocarcinoma, as well as the correlation between the clinical features of patients and mRNA levels of PD-L1 and components of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/phosphatase and tensin homolog (PTEN) pathways.
Methods: mRNA levels of PD-L1, PI3K, AKT, and PTEN in tumor and matched normal tissues of patients with EGFR mutation-positive lung adenocarcinoma were determined by real-time polymerase chain reaction.
Results: Twenty-three patients with EGFR mutation-positive lung adenocarcinoma were enrolled, and 46 samples (23 pairs of tumor and matched normal lung tissues) were collected. PD-L1 and AKT mRNA levels were higher in EGFR mutation-positive lung adenocarcinoma than in matched normal lung tissues (P = 0.047 and P = 0.046, respectively), whereas PI3K and PTEN mRNA levels were significantly lower in the cancerous tissues (P = 0.009 and P = 0.039, respectively). PD-L1 expression was positively correlated with PI3K/AKT signaling pathway activation. PD-L1 upregulation in lung adenocarcinoma was positively correlated with EGFR exon 19 mutations (P = 0.034). AKT mRNA upregulation was correlated with lymph node metastasis (P = 0.034). PTEN mRNA downregulation was correlated with high tumor staging and lymph node metastasis (P = 0.035 and P = 0.014, respectively).
Conclusion: Elevated PD-L1 mRNA expression in lung adenocarcinoma is associated with EGFR mutation and may be mediated through the PI3K-AKT pathway. EGFR exon 19 mutations closely correlate with increased PD-L1 mRNA expression. Increased AKT mRNA expression correlates with lymph node metastasis, while decreased PTEN mRNA levels correlate with advanced tumor stage and lymph node metastasis.

Keywords: Epidermal growth factor receptor, programmed cell death ligand 1, phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway, lung adenocarcinoma


How to cite this article:
Han K, Zhang Y. mRNA expression of programmed cell death ligand 1 and components of the phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway in epidermal growth factor receptor mutation-positive lung adenocarcinoma. J Can Res Ther 2019;15:914-20

How to cite this URL:
Han K, Zhang Y. mRNA expression of programmed cell death ligand 1 and components of the phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway in epidermal growth factor receptor mutation-positive lung adenocarcinoma. J Can Res Ther [serial online] 2019 [cited 2019 Sep 18];15:914-20. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/914/264298




 > Introduction Top


Lung cancer is currently the leading cause of cancer-related deaths worldwide.[1] Molecular targeted therapy drugs such as erlotinib have greatly improved the prognosis of patients with epidermal growth factor receptor (EGFR) mutation-positive or anaplastic lymphoma kinase mutation-positive non-small cell lung cancer (NSCLC).[2] However, the prognosis of lung cancer patients without these mutations remains poor.[3] Programmed cell death protein 1 (PD-1) is a receptor expressed on the surface of T-cells that regulates the activation and proliferation of T-cells; its ligand, PD ligand 1 (PD-L1), is overexpressed in NSCLC.[4] Binding of PD-L1 to PD-1 induces apoptosis or exhaustion of activated T-cells, and blocking this process promotes the antitumor activity of T cells.[4] PD-L1 overexpression in lung cancer cells is associated with the EGFR mutation status, which may be mediated by activation of the phosphatidylinositol 3-kinase-AKT (PI3K-AKT) pathway and phosphatase and tensin homolog (PTEN) deletion.[5],[6] Therefore, we sought to study the correlation between the aforementioned factors and their significance in the clinical features of patients by determining the mRNA levels of PD-L1, PI3K, AKT, and PTEN in EGFR mutation-positive NSCLC patients. We found significantly increased PD-L1 expression in lung adenocarcinoma tissue compared with that in the matched normal lung tissue. We also examined the mRNA levels of PI3K, AKT, and there is a positive correlation between PD-L1 and PI3K mRNA levels.


 > Methods Top


Specimen acquisition

The lung adenocarcinoma and matched normal tissue (>5 cm away from the edge of cancerous tissue) samples were collected by the Department of Thoracic Surgery in Xuan Wu Hospital of Capital Medical University from July 2016 to October 2017. The samples were fixed with 10% neutral formalin, embedded in paraffin, and serially sectioned into 3-μm sections. Pathologies of all samples were confirmed by a pathologist from our hospital. Tumor samples that were confirmed to be lung adenocarcinoma were screened by next-generation sequencing for mutations in exons 18, 19, and 21 of EGFR. Then, the mRNA levels of PD-L1, PI3K, AKT, and PTEN in EGFR mutation-positive lung adenocarcinoma and matched normal lung tissue samples were determined by real-time polymerase chain reaction (PCR).

Clinical and pathological data

Clinical data of included patients, including gender, age, smoking status, tumor stage, lymph node metastasis, pathological features (with or without nipple-like structures or micropapillae), and EGFR mutation sites (exons 18, 19, and 21), were recorded. Tumor staging was based on the tumor-node-metastasis classification (8th ed.ition, 2016) issued by the Union for International Cancer Control.

Statistical analysis

Statistical analysis was performed using SPSS 19.0 (IBM Corp. Armonk, NY: IBM Corp), and a t-test was used for comparison between groups. Correlation analysis was performed using the Spearman rank correlation test. Correlations with the clinical features of the patients were determined by logistic regression. P < 0.05 was considered statistically significant.


 > Results Top


General information on the samples

A total of 46 samples, including 23 lung adenocarcinoma samples that were confirmed to be EGFR mutation-positive and 23 matched normal lung tissue samples as controls, were included in this study.

Clinical features of the patients

The 23 patients included 10 males and 13 females; 8 of the patients were <60 years old and the other 15 were ≥60 years old; 7 were smokers and 16 were nonsmokers; 8 patients were in Stage I (34.8%), 3 were in Stage II (13%), 11 were in Stage III (47.8%), and 1 was in Stage IV (4.3%); 13 of the patients had lymph node metastasis and 10 had no lymph node metastasis; 14 had nipple-like structures or micropapillae and 9 had no nipple-like structures or micropapillae; 13 had mutations in exon 19 of EGFR, 9 had mutations in exon 21, and 1 had mutations in exon 18.

mRNA levels of programmed cell death ligand 1, phosphatidylinositol 3-kinase, AKT, and phosphatase and tensin homolog in lung adenocarcinoma with epidermal growth factor receptor mutations

We measured the mRNA levels of PD-L1, PI3K, AKT, and PTEN in lung adenocarcinoma tissues and matched normal lung tissues by fluorescence quantitative PCR. We found that the mRNA levels of PD-L1 and AKT in these EGFR mutation-positive lung adenocarcinoma tissues were significantly higher compared to those in the matched normal lung tissues (P = 0.047 and P = 0.046, respectively), whereas the mRNA levels of PI3K and PTEN were significantly lower than those in the normal tissues (P = 0.009 and P = 0.039, respectively), as shown in [Figure 1]. We observed that the results regarding PI3K were not consistent with those of previous studies and that this discrepancy may be related to the staging of the tumors included. Therefore, we tested Stage I + II and Stage III + IV tumors separately and found that PI3K mRNA expression tended to be higher in early (Stage I + II) lung adenocarcinoma tissues than in normal tissues (P = 0.754) but was significantly lower in advanced (Stage III + IV) lung adenocarcinoma tissues than in normal tissues (P = 0.0003), as shown in [Figure 2].
Figure 1: Comparison of the expression of various factors in lung adenocarcinoma tissues with those in normal lung tissues

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Figure 2: Comparison of phosphatidylinositol 3-kinase mRNA expression in epidermal growth factor receptor-positive lung adenocarcinoma tissues and normal lung tissues at different stages

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Correlations between programmed cell death ligand 1, phosphatidylinositol 3-kinase, AKT, and phosphatase and tensin homolog mRNA expression in lung adenocarcinoma with epidermal growth factor receptor mutations

We observed in these lung adenocarcinoma tissues that PD-L1 mRNA expression was positively correlated with that of PI3K (correlation coefficient = 0.522, P = 0.011) and that the mRNA levels of PI3K and AKT were also positively correlated, as shown in [Table 1].
Table 1: Correlations between various factors in epidermal growth factor receptor mutation-positive lung adenocarcinoma tissues

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Correlations between the mRNA levels of programmed cell death ligand 1, phosphatidylinositol 3-kinase, AKT, and phosphatase and tensin homolog and clinical features of the patients

Statistical analysis demonstrated that PD-L1 mRNA levels were correlated with EGFR mutations in exon 19 in patients who showed increased PD-L1 mRNA expression (P = 0.034). Increased AKT mRNA expression was correlated with lymph node metastasis (P = 0.034). Decreased PTEN mRNA expression was correlated with high tumor staging and lymph node metastasis (P = 0.035 and P = 0.014, respectively), as shown in [Table 2] and [Table 3].
Table 2: Relationships among programmed cell death ligand 1, phosphatidylinositol 3-kinase, and clinical characteristics of epidermal growth factor receptor-mutant lung adenocarcinoma tissues

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Table 3: Relationships among protein kinase B, phosphatase and tensin homolog, and clinical characteristics of epidermal growth factor receptor-mutant lung adenocarcinoma tissues

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 > Discussion Top


PD-L1 is a member of the B7 protein family and an important inhibitory molecule of T-cell activation.[7],[8] Studies have shown that many tumor cells express high levels of PD-L1 on their surfaces, which binds to PD-1 on the surface of T-cells to inhibit T-cell proliferation and activation; this ultimately leads to an impaired immune response, immune escape of tumor cells, and increased tumor growth, invasion, and metastasis.[9],[10] Recent studies have demonstrated that the expression of PD-L1 is related to the EGFR mutation status in NSCLC and may be mediated by the PI3K/AKT/PTEN pathway. However, the mechanism underlying such regulatory effects is still not fully understood.[5],[6] Some scholars have suggested that mutated EGFR may become ligand -independent, leading to its self-phosphorylation and constitutive activation. Meanwhile, mutated EGFR may lose certain domains involved in the downregulation of the receptor, leading to constitutive activation of downstream signaling pathways, such as PI3K-AKT. The activated PI3K-AKT pathway plays a central role in the translation of interferon-γ), which is a key regulator of PD-L1 transcription.[11] Increased PD-L1 expression has been observed in HIV-infected macrophages and dendritic cells, whereas blocking PI3K-AKT signaling reversed this effect.[12] In this study, we examined PD-L1 mRNA expression in EGFR mutation-positive lung adenocarcinoma and matched normal lung tissues with fluorescence quantitative PCR and found significantly increased PD-L1 expression in lung adenocarcinoma tissue compared with that in the matched normal lung tissue (P = 0.047). We also examined the mRNA levels of PI3K, AKT, and PTEN. Spearman's rank correlation test suggested a positive correlation between PD-L1 and PI3K mRNA levels (correlation coefficient = 0.522, P = 0.011), suggesting that increased PD-L1 expression in lung adenocarcinoma with EGFR mutations may be mediated by the PI3K/AKT pathway. Logistic regression analysis demonstrated that increased PD-L1 mRNA expression was correlated with mutations in exon 19 of EGFR, so we speculated that mutations in exons 19 and 21 of EGFR may differentially affect the phosphorylation of downstream pathways such as the PI3K/AKT pathway, which leads to differences in PD-L1 expression. A literature review showed that Zhang et al.[13] reported that NSCLC patients with mutations in exons 19 and 21 of EGFR may respond differently to gefitinib, and both types of patients showed decreased phosphorylation of EGFR, AKT, and extracellular-regulated kinase when treated with gefitinib, but tumors with exon 19 mutations were more sensitive than those with exon 21 mutations. A meta-analysis in 2014 showed that NSCLC patients with mutations in exon 19 achieved longer progression-free survival when treated with first-line EGFR-tyrosine kinase inhibitors (TKIs) than those with mutations in exon 21.[14] These facts all suggest different clinical effects of exon 19 and 21 mutations of EGFR, but further experimental studies are required to clarify how they differentially affect PD-L1 expression. Some scholars have found that the expression of PD-L1 in breast cancer is closely related to the type of tumor tissue, tumor stage, and lymph node metastasis. This study also aimed to achieve the same results; however, considering the sample size, no positive results were obtained. We will increase the sample size in subsequent experiments to further confirm.[15]

PI3K catalyzes the phosphorylation at D3 of phosphatidylinositol and can be classified into three groups according to differences in structure and function. Group IA PI3Ks are the most extensively studied and consist of the p85 regulatory subunit encoded by the PIKR1 gene and the p110 catalytic subunit encoded by the PIK3CA gene; these proteins show both protein kinase and lipid kinase activities.[13],[14] PI3Ks are primarily activated either by the direct binding of Ras to p110 or by the phosphorylation of tyrosine residues of growth factor receptors such as EGFR and c-MET, which results in changes in the structure of the dimers and activation of PI3K.[16] Our results demonstrated that PI3K and AKT mRNA levels are positively correlated (correlation coefficient = 0.568, P = 0.005), which were consistent with the results of previous studies. Surprisingly, we observed lower PI3K mRNA expression in lung adenocarcinoma tissues than in matched normal tissues (P = 0.009). Therefore, we separately compared PI3K mRNA levels in Stage I + II and Stage III + IV lung adenocarcinoma samples with those in matched normal lung tissues. The results suggested that the PI3K mRNA levels tended to be higher in early-stage EGFR mutation-positive lung adenocarcinoma tissues than in matched normal lung tissues but were significantly lower in late-stage EGFR mutation-positive lung adenocarcinoma tissues than in matched normal tissues.[17],[18] We speculated that PI3K expression may be selected against during the growth and invasion of adenocarcinoma, but the exact mechanism requires further investigation.

AKT, also known as protein kinase B (PKB), is a serine/threonine kinase and is one of the major downstream effector molecules of PI3K that is involved in the regulation of various cell functions by phosphorylating various transcription factors (e.g., nuclear factor kappa-B and mammalian target of rapamycin).[19],[20] Phosphorylation of AKT is critical for the activation of the PI3K-AKT pathway. Studies have shown that AKT activation is closely related to tumor metastasis, while inhibition of AKT phosphorylation reduces invasion and metastasis of gastric cancer and breast cancer cells.[20] Our results suggested that AKT mRNA levels were higher in the EGFR mutation-positive lung adenocarcinoma tissues than in matched normal lung tissues (P = 0.046), and tumors with lymph node metastasis more frequently showed increased AKT mRNA expression than those without metastasis (P = 0.034), further suggesting a correlation between AKT activation and invasion and lung cancer metastasis.

PTEN encodes a 53 kDa phosphatase and is the first one found to have dual-specific phosphatase activity. PTEN acts as a tumor suppressor gene, and the loss of PTEN has been observed in many tumors.[21] In the PI3K/AKT pathway, when PI3K is activated, its catalytic subunit p110 specifically phosphorylates the D3 site of phosphoinositide, converting phosphatidylinositol 2-phosphate (PIP2) to phosphatidylinositol 3-phosphate (PIP3). PIP3 then acts as a secondary messenger to further activate downstream effector molecules promoting cell proliferation, migration, and malignant transformation.[22],[23] PTEN has phosphatase activity and can dephosphorylate PIP3 to PIP2 so that PI3P loses its messenger function and the PI3K-AKT signaling pathway is deactivated. PTEN mutation or deletion causes the accumulation of intracellular PIP3 and sustained activation of AKT, which leads to the inhibition of apoptosis and the continuous growth of cells, eventually resulting in malignant transformation.[24],[25] Our results showed that the expression of PTEN mRNA in lung adenocarcinoma tissues with EGFR mutations was significantly lower than that in matched normal lung tissues (P = 0.039), suggesting a close relationship between PTEN downregulation and malignant transformation of NSCLC. It is known that the abnormal activation of PTEN activates downstream AKT. However, it is notable that no significant relationship was observed between the mRNA levels of PD-L1 and PTEN even though AKT is significantly related to PD-L1 expression; this may be attributed to two facts. First, overactivation of the PI3K-AKT pathway is caused by several factors, and the deletion of the PTEN gene is only one of them, which suggests a weak relationship between PTEN and PD-L1.[26] Second, subgroup analysis was not performed due to insufficient sample size; if the sample size was large enough, we could have compared the expression of PTEN mRNA in lung adenocarcinoma tissues with or without the overexpression of PD-L1 mRNA. The exact mechanism requires further investigation. Outcomes of our experiment showed that the downregulation of PTEN mRNA expression was also correlated with high tumor staging and lymph node metastasis (P = 0.035 and P = 0.014, respectively). PTEN mRNA levels further decreased in advanced lung adenocarcinoma tissues with lymph node metastasis, suggesting that PTEN is gradually decreased during the transformation to malignancy and from the early to late stages until invasion and metastasis.

In summary, our results suggest that the expression of PD-L1 mRNA is associated with EGFR mutation status in lung adenocarcinoma tissues and that the increased PD-L1 mRNA expression may be mediated by the activation of the PI3K-AKT pathway. This finding has clinical significance; for example, NSCLC patients with EGFR mutations may achieve better treatment response if supplemented with PD-L1 inhibitors. Moreover, when tumors incur mutations in genes such as T790 or KRAS, they develop resistance to EGFR-TKIs; thus, immune therapy may become an attractive alternative mode of treatment.[27],[28] However, some scholars have found that the efficacy of PD-L1 inhibitors in patients with EGFR mutations is different. Some believe that this result may be due to the low mutation burden associated with EGFR mutations. Others believe that this phenomenon may be related to the method for detecting the degree of expression of PD-L1. At present, immunohistochemical methods are commonly employed, but different cutoff values and scoring systems have been used in different clinical trials. This may explain why the results are controversial, thus calling for the need to find better diagnostic markers.[29] In our experiment, we also observed that the upregulation of PD-L1 mRNA expression was closely related to mutations in exon 19 of EGFR, and PI3K mRNA expression was lower in lung adenocarcinoma tissues than in matched normal lung tissues; however, the mechanism underlying this needs further study. AKT mRNA expression is elevated in lung adenocarcinoma tissues, and its upregulation in lung adenocarcinoma is associated with lymph node metastasis. PTEN mRNA expression was lower in lung adenocarcinoma tissues than in matched normal lung tissues; moreover, it was further decreased in advanced tumors and in those with lymph node metastasis. Therefore, these genes can be used as diagnostic markers in clinical practice to obtain information about tumor staging, lymph node metastasis, and prognosis; however, they will need to be further verified in future experiments.


 > Conclusion Top


  1. In contrast to the normal lung tissue, the expressions of PD-L1, AKT in tumor tissue were up-regulated, while the expressions of PI3K, PTEN were down-regulated.
  2. The expression level of PD-L1 was positively correlated with the PI3K-AKT pathway.
  3. Up-regulated expression of PD-L1 in tumor tissue was correlated with the mutation of 19 exon of EGFR. The up-regulated expression of AKT possibly indicated its correlation with the lymph node metastasis. The down-regulated mRNA expression of PTEN was correlation with the tumor staging and lymph node metastasis.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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