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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 138-144

Phosphatase and tensin homolog protein may be linked to lymph node metastasis and tumor node metastasis staging in nonsmall cell lung cancer


Department of Emergency, The First Affiliated Hospital of Jilin University, Changchun 130021, Jilin Province, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Ming-Li Sun
Department of Emergency, The First Affiliated Hospital of Jilin University, Changchun 130021, Jilin Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.165865

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 > Abstract 


Background: This study aims to investigate the correlations of positive rate of phosphatase and tensin homolog (PTEN) protein with lymph node metastasis (LNM) and tumor node metastasis (TNM) staging of nonsmall cell lung cancer (NSCLC) patients by conducted a meta-analysis.
Materials and Methods: Covering several electronic databases (Embase, Cochrane Library, China BioMedicine, China National Knowledge Infrastructure, PubMed, and Web of Science), published papers eligible for enrollment in the current meta-analysis had to fulfill our predefined selection criteria. Odds ratios (ORs) with their 95% confidence interval (95%CI) were aggregated utilizing comprehensive meta-analysis 2.0 software (Biostatic Inc., Englewood, New Jersey, USA).
Results: Twelve cohort studies with a total of 419 NSCLC patients were incorporated into the current meta-analysis. A decreased positive rate of PTEN protein was detected in NSCLC patients with TNM stage III-IV rather than those patients with TNM stage I-II (OR = 0.454, 95%CI = 0.338–0.610, P < 0.001). PTEN in NSCLC patients without LNM expressed higher than that in the patients with LNM (OR = 0.532, 95%CI: 0.299–0.948, P = 0.032). Ethnicity-stratified analysis demonstrated a negative relationship between positive rate of PTEN protein and TNM staging of NSCLC among both Asians and Caucasians (both P < 0.05). However, we found no significant association between positive rate of PTEN protein and LNM among Asians and Caucasians (both P > 0.05).
Conclusion: Our findings indicate that decreased positive rate of PTEN protein may be linked to TNM staging and LNM in NSCLC, and it could be an important diagnostic biomarker of NSCLC.

Keywords: Lymph node metastasis, meta-analysis, nonsmall cell lung cancer, phosphatase and tensin homolog, tumor node metastasis stage


How to cite this article:
Ji ZY, Li HF, Lei Y, Rao YW, Sun ML, Wang XW, Zhang YL. Phosphatase and tensin homolog protein may be linked to lymph node metastasis and tumor node metastasis staging in nonsmall cell lung cancer. J Can Res Ther 2018;14, Suppl S1:138-44

How to cite this URL:
Ji ZY, Li HF, Lei Y, Rao YW, Sun ML, Wang XW, Zhang YL. Phosphatase and tensin homolog protein may be linked to lymph node metastasis and tumor node metastasis staging in nonsmall cell lung cancer. J Can Res Ther [serial online] 2018 [cited 2019 Aug 19];14:138-44. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/138/165865




 > Introduction Top


Lung cancer, the common cause of cancer death worldwide, is frequently diagnosed both in men and women, which caused over 1.4 million deaths in 2008.[1],[2] It usually consists of two types which are small cell lung cancer and nonsmall cell lung cancer (NSCLC).[3] As the most common type of lung cancer, NSCLC accounts for approximately 80% to 90% of the total.[4] The report presented by the relevant authority showed that nearly 1.6 million new NSCLC cases increased in 2008.[5] For the patients with stage III NSCLC, local and distant treatment failures are common, and the majority of them had a poor prognosis with a low 1-year, 3-year, and 5-year survival rate.[6],[7] Generally speaking, smoking habits is the main reason of NSCLC, but this does not exclude the nonsmokers.[8] The current pattern of lung cancer therapy primarily relies on the TNM disease staging.[9] Combination chemotherapy, chemoradiation survival, and radiation therapy are common treatments with advanced NSCLC.[10] However, despite the improved medical technologies, the recovery rate is still low on account of difficulties of early diagnosis and high risk of metastasis, as well as resistance of therapy.[11],[12] Therefore, identification of biologic markers for NSCLC is unceasingly unveiled to satisfy the pressing need of improving survival of advanced NSCLC patients.[13]

Phosphatase and tensin homolog (PTEN), also known as MMAC1, is involved in multiple and modulating cell growth processes, cell migration, and apoptosis.[14] PTEN has antagonizing activity to protein tyrosine kinase which also participates in regulating the phosphoinositide 3-kinase pathway.[15] PTEN is also of great importance in the regulation of cell migration, metabolism, proliferation, apoptosis, and survival.[16],[17] Down-regulation of PTEN expression has been found in various cancers including lung carcinoma, prostate, breast, brain, endometrial, glioblastoma, and melanoma.[18],[19],[20],[21] The loss of PTEN function is also frequently found in NSCLC; poor differentiation, distant metastasis, lymph node involvement, and late stages are probably correlated with PTEN expression of NSCLC.[22] In general, down-regulation of PTEN protein expression level correlated significantly with the imbalances of PI3K/Akt signal pathway has played a certain role in the development of NSCLC and maintains the malignant biological behavior of tumors, and thus promotes the progress of the tumor.[23],[24] In addition, down-regulation of PTEN expression is linked with the infiltration and the metastasis in NSCLC, the patients with the moderate, low, or negative PTEN protein expression is more likely to contribute to the lymph node metastasis (LNM).[25] Previous studies indicated that the lack of PTEN expression is closely related to advanced stage, and LNM and PTEN could regulate tumor progression, metastasis of NSCLC.[17],[23] However, other studies only reported that alteration of PTEN plays an essential role in pathogenesis and carcinogenesis of NSCLC, and no further clarification on LNM and TNM staging of NSCLC patients.[1],[23] The aim of this study is to understand the correlations of positive rate of PTEN protein with LNM and TNM staging of NSCLC patients.


 > Materials and Methods Top


Data sources and keywords

With the application of computerized databases (Embase, Cochrane Library, China BioMedicine, China National Knowledge Infrastructure, PubMed, and Web of Science) updated in May 31, 2014, those published papers which assessed the correlations of positive rate of PTEN protein with TNM staging and LNM of NSCLC were obtained, utilizing selected common keywords (“lung neoplasms” or “carcinoma, bronchogenic” or “adenocarcinoma, bronchioloalveolar” or “small cell lung carcinoma” or “carcinoma, nonsmall cell lung” or “lung cancer” or “lung carcinoma” or “pulmonary carcinoma” or “pulmonary cancer” or “pulmonary neoplasms” or “lung tumor” or “pulmonary tumor” or “lung neoplasms” or “carcinoma, bronchogenic” or “bronchogenic carcinomas” or “bronchial carcinomas” or “bronchogenic tumor” or “bronchogenic cancer” or “bronchial neoplasms” or “bronchial cancer” or “bronchial tumor” or “bronchogenic neoplasms” or “adenocarcinoma, bronchioloalveolar” or “alveolar cell carcinoma” or “alveolar carcinomas” or “bronchioloalveolar carcinomas” or “bronchioloalveolar carcinomas” or “alveolar adenocarcinomas” or “bronchiolar carcinomas” or “small cell lung carcinoma” or “small cell lung cancer” or “oat cell lung cancer” or “small cell cancer of the lung” or “carcinoma, small cell lung” or “oat cell carcinoma of lung” or “SCLC” or “nonsmall cell lung carcinomas” or “nonsmall cell lung cancer” or “nonsmall cell lung carcinoma” or “NSCLC”) and (“PTEN protein, human” or “MMAC1” or “PTEN phosphohydrolase” or “PTEN phosphohydrolase” or “PTEN phosphatase” or “phosphatase, PTEN” or “PTEN protein” or “MMAC1 protein” or “MMAC1” or “PTEN”) and (“humans”). The published language was unlimited. Bibliographies of related papers were further looked through manually for additional potential relevant papers.

Study selection

The inclusion criteria for enrolling studies included: (1) Patients must have pathologically confirmed NSCLC; (2) human-associated cohort studies focus on the role of PTEN protein in TNM staging and LNM of NSCLC; (3) available data for positive rate of PTEN protein, TNM staging and LNM status of NSCLC and sample number must be supplied; (4) the minimum number of samples must be >50; and (6) published studies with full text. However, when the extracted studies exceeded 50% similarities with two or more articles, we merely chose the one who has the most comprehensive population. Also, the enrolled studies that published by the same authors were included with the presence of the latest or complete data.

Data extraction

The credibility was enhanced through the method of extracting information by two investigators from all the retrieved papers separately. The following data were extracted:First author, time of publication, sample, age, gender, country, ethnicity, source of samples, detection method for positive rate of PTEN protein, and positive rate of PTEN protein in NSCLC patients with different TNM staging and LNM status.

Quality assessment

Critical appraisal skill program (CASP) criteria were used by two authors independently to judge the quality of questioned studies.[26] The specific 12 items in CASP were displayed as follow: (1) Whether the study addressed a clearly focused issue (CASP01); (2) whether the cohort was recruited in an acceptable way (CASP02); (3) whether the exposure was accurately measured to minimize bias (CASP03); (4) whether the outcome was accurately measured to minimize bias (CASP04); (5) (a) whether the authors identified all important confounding factors, (b) whether the authors have taken account of the confounding factors in the design and/or analysis (CASP05); (6) whether the follow-up of subjects was complete enough or long enough (CASP06); (7) whether the results of this study were complete (CASP07); (8) whether the results were precise (CASP08); (9) whether the results were creditable (CASP09); (10) whether the results could be applied to the local population (CASP10); (11) whether the results of this study fitted with other available evidence (CASP11); and (12) whether there were further implications of this study for practice (CASP12).

Statistical analysis

For TNM stage I-II versus TNM stage III-IV and with LNM versus without LNM categories of positive rate of PTEN protein, the summary odds ratios (ORs) with 95% confidence interval (95%CI) were applied to calculate the effect size for each study with the utilization of Z-test. The ORs for TNM staging and LNM were aggregated utilizing comprehensive meta-analysis 2.0 software (Biostatic Inc., Englewood, New Jersey, USA) by two investigators separately. Random-effect model was employed with the existence of heterogeneity among studies while fixed-effects model was applied when fine homogeneity was observed. The Cochran's Q-statistic (P < 0.05 was deemed to be statistically significant) was chosen to evaluate the heterogeneity among all the enrolled studies, which was further measured by I2 test (0%, no heterogeneity; 100%, maximal heterogeneity) due to the consideration of low statistical power of the Cochran's Q-statistic.[27],[28] Under the situation of heterogeneity existing, the potential effect modification was explored through the meta-regression and subgroup meta-analyses by ethnicity and detection method. The results could affect the whole result if a single study was deleted one by one and was assessed by sensitivity analysis. The funnel plot was applied to assess whether there existed publication bias. Whether there was publication bias in the current meta-analysis was further verified by classic fail-safe N and Egger's linear regression test.[29]


 > Results Top


Included studies

[Figure 1] presents the steps of selecting study. A total of 487 reports were retrieved initially, and 172 papers were kept after removing of two duplicates, 96 letters, reviews, or meta-analysis, 107 nonhuman studies, and 110 studies unrelated to research topics. Furthermore, additional 158 studies were excluded for not cohort study (n = 45), not relevant to PTEN protein (n = 51), or irrelevant to NSCLC (n = 62). In the final selection step, 12 of 14 studies were identified with two articles removed for not supplying enough information. Seven studies with a total of 1395 NSCLC patients were performed in Asians (China, Japan, Korea, and Turkey),[1],[2],[3],[23],[30],[31],[32] and five studies were in Caucasians (USA, France, and Greece).[7],[8],[25],[33],[34] All samples in the papers, enrolled in our current meta-analysis, were from tissues. The detection methods mainly included streptavidin-peroxidase (SP), avidin biotin complex (ABC), EnVision, LabVision, streptavidin biotin-peroxidase complex (SABC), and enzyme-linked immunosorbent assay (ELISA). The methodological quality of included studies was evaluated by CASP criteria [Figure 2].
Figure 1: Flowchart showing literature search and study selection. Twelve clinical cohort studies met the inclusion criteria were included in this meta-analysis

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Figure 2: The methodological quality of included studies was evaluated by critical appraisal skill program criteria

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Main findings of meta-analyses

As shown in [Figure 3], ORs for TNM staging were available from eight studies and ORs for LNM from nine studies. The pooled ORs revealed a decreased expositive rate of PTEN protein in the NSCLC patients TNM stage III-IV rather than in the patients with TNM stage I-II (OR = 0.454, 95%CI = 0.338–0.610, P < 0.001). The pooled ORs also suggested that PTEN protein in the NSCLC patients without LNM expressed higher when compared to that in the patients with LNM (OR = 0.532, 95% CI: 0.299–0.948, P= 0.032). Subgroup analysis based on ethnicity demonstrated a negative relationship between positive rate of PTEN protein and TNM staging of NSCLC among both Asians and Caucasian population (Asians: OR = 0.397, 95%CI = 0.271–0.580, P < 0.0001; Caucasians: OR = 0.559, 95%CI = 0.349–0.894, P= 0.015). As for LNM of NSCLC and positive rate of PTEN protein, no significant correlation between them was observed in Asian and Caucasians (Asians: OR = 0.509, 95%CI = 0.230–1.124, P= 0.095; Caucasians: OR = 0.564, 95%CI = 0.214–1.490, P= 0.248) [Figure 4].
Figure 3: Forest plots for the differences of phosphatase and tensin homolog protein expression in lymph node metastasis and tumor node metastasis staging of nonsmall cell lung cancer patients

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Figure 4: Subgroup analyses for the differences of phosphatase and tensin homolog protein expression in lymph node metastasis and tumor node metastasis staging of nonsmall cell lung cancer patients

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Sensitivity analysis and publication bias

The sensitivity analysis results implied that the overall statistical significance was unchangeable in some included studies when any single study was omitted except for eliminating the studies of Qi et al., Cao, Yun et al., Panagiotou et al. (2012), Kim et al., and Goncharuk et al. for with or without LNM [Figure 5]. Funnel plots, classic fail-safe N and Egger's linear regression test, were inspected for indication of publication bias, and confirm the reliability of original analysis results (both P < 0.001) [Figure 6].
Figure 5: Sensitivity analyses of the summary odds ratio coefficients for the differences of phosphatase and tensin homolog protein expression in lymph node metastasis and tumor node metastasis staging of nonsmall cell lung cancer patients

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Figure 6: Funnel plots of publication biases for the differences of phosphatase and tensin homolog protein expression in lymph node metastasis and tumor node metastasis staging of nonsmall cell lung cancer patients

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 > Discussion Top


The meta-analysis was carried out with the main aim of the exploration the associations of positive rate of PTEN protein with LNM and TNM staging of NSCLC. In this analysis, we finally found out that decreased expression of PTEN was significantly correlated with tumor TNM staging and LNM of NSCLC, suggesting that PTEN expression may play a crucial role in tumor cell proliferation and invasion in NSCLC, and has a value in predicting NSCLC onset. To the best of our knowledge, PTEN was considered as the candidate of tumor-suppressor gene involving the regulation of cell cycle including cell growth, survival, and differentiation; thereby, it was speculated that aberrant expression of PTEN is observed in NSCLC tissues of patients by mediating p27 activation to affect tumorigenesis.[34] There was report illustrating that several target genes including PTEN modulated by ubiquitin carboxylterminal hydrolase 22 expression detected in NSCLC patients focus on stimulating cell invasion and metastasis, thus postulating a possibility that PTEN serum levels are related to NSCLC histologic grades and lymphatic metastasis.[1] It was proved that PTEN loss in NSCLC tissues could affect the balance of oncogenes and anti-oncogenes leading to cancer with continuous proliferation and differentiation, which was implicated in late stage of NSCLC and poor treatment outcome in patients.[2] Furthermore, the pathogenesis and TNM stage of NSCLC was more connected with the mutual interaction between biological and clinical markers such as PTEN, P-AKT, implying that reduced PTEN expression might result in the increased activities of P-AKT pathway to prevent cell apoptotic process, consequently accounting for the carcinogenesis.[23] Other than that, the explanation for the functional mechanism of PTEN in NSCLC tissues might be that NSCLC patients were discovered with epidermal growth factor receptor variant responsible for enhancing PTEN activities, suggesting that down-regulated PTEN expression has an effect on LNM of NSCLC cells and terrible survival rates.[30] On the basis of above opinions of published documents, our results demonstrated that the lower expression of PTEN is more frequent in advanced stage of NSCLC, and PTEN can be served as a predictor in NSCLC risk. Yanagawa et al. pointed out an opinion in line with our study that malignant cancer in NSCLC patients were amplified and aggravated attributable to the loss of PTEN expression, eventually shortening survival times of NSCLC patients.[3] Panagiotou et al. also reported that PTEN deregulation might be associated with metastatic process of NSCLC, and the detection of PTEN expression might therefore be valuable and significant for preventing disease condition deterioration of NSCLC.[25]

Also, ethnicity-stratified analysis reflected that lower PTEN expression was related with TNM stage of NSCLC patients among Asians and Caucasians, manifesting that race differences might not be the factor of heterogeneity in the relationship research. PTEN expression has no significant association with LNM of NSCLC patients both in Asians and Caucasians. To sum up, our results of the meta-analysis proved the relationship between PTEN expression and pathological features in NSCLC such as TNM staging and defined the values of PTEN in the prediction of NSCLC prognostic outcome.

To sum up, our data suggested that decreased positive rate of PTEN protein may be linked to TNM staging and LNM in NSCLC. However, the sample size in our meta-analysis was relatively small, and some of our studies have a relatively higher numbers, but others have a relatively low numbers, which would have an adverse influence in the statistical power to detect the differences between groups. Additionally, the detection of PTEN protein in included studies used different methods, including SP, EnVision, LabVision, SABC, ELISA and ABC, the different detection mode, and standards of different methods would lead to the existence of heterogeneity, which may further affect our overall results. Due to the above limitation, further larger sample studies with various populations are required to evaluate the biological significance of PTEN and to confirm the final findings of our results.

Acknowledgments

We would like to acknowledge the helpful comments received on earlier drafts of this paper from our reviewers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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