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Abstract

BACKGROUND:

This study was carried out to investigate the correlation between CD133 and non-small cell lung cancer (NSCLC) clinicopathological features and its impact on survival of the patients with NSCLC.

METHODS:

In the first, we detected the level and localization of CD133 protein in NSCLC specimens and confirmed that CD133 expression was closely linked to poor prognosis of NSCLC. Secondly, TCGA genomic data for LUNG (Provisional) was retrieved and analyzed for genetic alterations of CD133 in different lung cancer subtypes. In the last, a comprehensive literature search for relevant studies published up to December 2015 was performed using Medline, EMBASE Classic $+$ EMBASE, and The Cochrane Central Register of Controlled Trials.

RESULTS AND CONCLUSION:

Both our experimental results and pooled results of previous studies indicated that CD133 may be used as a prognostic marker for the patients with NSCLC. However, more studies are required to evaluate CD133 potential use in predicting patients’ outcome.

Keywords

Non-small-cell lung cancer histology differentiation hazard ratio survival

1. Introduction

Figure 1.

CD133 expression in NSCLC. A. The level of CD133 mRNA was higher in lung cancer tissue than matched normal tissue ( $P<$ 0.05). B. Western blot analysis for CD133 expression in specimens. C. The level and localization of CD133 protein was measured in specimens using IHC. D. Kaplan-Meier curve survival analysis indicating that the NSCLC patients with CD133 expression had a poorer survival than those without its expression.

Lung cancer continues to be the most commonly diagnosed cancer as well as the leading cause of cancer death in the world [1]. A major problem in finding treatments for lung cancer is the frequent resistance to drugs. Early detection of non-small-cell lung cancer (NSCLC) and accurate prognostic risk assessment could improve patient outcome. For example, Takahashi et al., [2, 3] confirmed that DiAcSpm/cutoff ratio (DASr) could be a useful biomarker for detecting NSCLC and predicting prognosis.

Human CD133, also known as prominin-1, a 5-transmembrane domain glycoprotein, was originally identified as a cell surface antigen present on hema- topoietic stem cells [4]. Eramo et al. [5] demonstrated the existence of CD133 ${}^{+}$ cells with stem cell properties in human lung cancers. In specimens of human non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), an enrichment of CD133 ${}^{+}$ cells is found in these tumors compared with healthy lungs [6]. Although the function of CD133 is still unknown, more and more studies showed that CD133 is a prognostic marker for survival of non-small cell lung cancer patients [7, 8, 9]. However, the relation between CD133 and the clinical pathologic features of NSCLC remains controversial [10].

This study was carried out to determine the association between CD133 and the common clinical and pathologic features of NSCLC both by our experimental results and pooled results of previous studies.

2. Materials and methods

2.1 Subjects

Experiments and methods of this study were conducted in accordance with ethical principles stated in the Declaration of Helsinki. The Ethics Committee of Liaoning Medical University reviewed and approved this study and a written informed consent was required from participants or caregivers. A total of 132 patients with NSCLC were obtained from the First Hospital of China Medical University (Jan. 2007 to Dec. 2010). None of the patients underwent radiotherapy or chemotherapy before the operation. Informed consent was provided by all patients according to the Helsinki Declaration. The mean age of patients at the time of surgery was 56 years (range of 38–77 years). Sex, age, tumor size, histological type, tumor differentiation, and TNM stage are also collected in this study.

2.2 RT-PCR

Total RNA was isolated from human tissues using an RNeasy Mini Kit (Biomed, Beijing, China). cDNA was reverse transcribed with 1 $\mu$ g of total RNA using a TaKaRa Reverse Transcription Kit (TaKaRa, Dalian, China) and was amplified using the following primers. CD133 primers were 5’-ACCGACTGAGACCCAAC ATC-3’ (sense) and 5’-GGTGCTGTTCATGTTCTCC A-3’ (antisense). GAPDH primers were 5’-AGAAGG CTGGGGCTCATTTG-3’ (sense) and 5’-AGGGGCC ATCCACAGTCTTC-3’ (antisense) and used as an internal control. The PCR products were electrophoresed on a 1.5% agarose gel, and visualized by ethidium bromide staining under a UV imaging system (UVP, LLC, Upland, CA, USA).

Table 1
Relationship between CD133 and the clinicopathological parameters of patients with NSCLC

Clinicopathological	CD133
features	n	Positive	Negative	$\chi^{2}$	P
Sex				0.260	0.608
Male	72	50	22
Female	60	45	15
Age (years)				0.013	0.909
$<$ 60	90	65	25
$\geqslant$ 60	42	30	12
Differentiation				49.80	0.000
Well or moderate	44	14	30
Poor	88	81	7
Lymphatic invasion				43.29	0.000
$-$	53	21	32
$+$	79	74	5
Venous invasion				40.67	0.000
$-$	33	9	24
$+$	99	86	13
Histological type				0.083	0.959
Squamous cell	40	29	11
Adenocarcinoma	51	36	15
Large cell	41	30	11
Tumor size				2.561	0.109
$<$ 3 cm	70	55	15
$\geqslant$ 3 cm	62	40	22
pN category				7.503	0.057
pN0	32	25	7
pN1	36	28	8
pN2	43	32	11
pN3	21	10	11

Abbreviations: $\chi^{2}$ Chi-square distribution.

2.3 Western blotting

Specimens were lysed using lysis buffer (50 mM Tris-HCl, pH $=$ 7.4, 150 mM NaCl, 1% Triton X-100, 0.1% sodium dodecyl sulfate (SDS), 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM Na ${}_{3}$ VO ${}_{4}$ , 1 mM NaF, protease inhibitor cocktail). The extracts were incubated on ice for 20 min, centrifuged at 12,000 $\times$ g for 20 min at 4 ${}^{\circ}$ C, and supernatants collected. Protein concentrations were determined using Bradford assay (Bio-Rad, Hercules, CA), and proteins were resolved by 10% Bis-Tris gel electrophoresis, transferred to a nitrocellulose membrane, and western blot analysis performed. Anti-CD133 (LifeSpan BioSciences Inc., WA, USA) and anti- $\beta$ -actin (Santa Cruz Biotechnology Inc., CA, USA) were used as primary antibody.

2.4 Immunohistochemical studies (IHC)

We used immunohistochemical staining method in this study, according to the literature [11]. All the cases of lung cancer tissue samples underwent Envision two-step immunohistochemical staining. Primary antibody, CD133 (LifeSpan BioSciences Inc.), was applied at 4 ${}^{\circ}$ C overnight. Secondary antibody of Dako EnVision was purchased from Dako Corporation (Carpinteria, CA, USA). Positive reactions were visualized using 3, 3’-diaminobenzidine tetrahydrochloride (DAB; Beyotime, Beijing, China), followed by counterstaining with hematoxylin (Beyotime). Evaluation of sections was carried out by Wang and Xia. The staining intensity was scored using a four-tier scale: 0, negative; 1+, weak; 2+, moderate; 3+, strong. High IHC expression level was defined as a staining intensity of 2+ or 3+ in more than 25% of the tumor cells, and the other cases were considered as having low IHC expression levels.

Figure 2.

Expression differences of CD133 mRNA in TCGA LUNG set (provisional) associated with clinical pathological features. The query process was performed using the cBioPortal online tools (www.cbioportal.org) and Kaplan-Meier plotter analysis (http://kmplot.com/analysis/).

Table 2

Characteristics of studies included in the meta-analysis

First author	Year	Coutry	Cases	Ages (mean)	Cancer type	Median follow-up	DFS	OS	Method
						period
Le [7]	2013	China	30	61.1 y	NSCLC	No data available	No data available	0.179	qPCR
Alamgeer [8]	2013	Australia	267	70 y	NSCLC ${}^{*}$	60.0 months	No data available	8.5	IHC
Mizugaki [9]	2013	Japan	161	No data available	NSCLC	110.0 months	No data available	3.157	RT-PCR
Salnikov [10]	2010	Germany	88	No data available	NSCLC	No data available	No data available	In figure	IHC
Janikova [13]	2010	Czech	116	No data available	NSCLC	No data available	In figure	In figure	IHC
Pirozzi [14]	2013	Italy	45	74.2 y	NSCLC	16.3 months	In figure	No data available	IHC
Herpel [15]	2011	Germany	133	63.7 y	NSCLC ${}^{*}$	53.8 months	0.6	0.6	IHC
Wu [16]	2012	China	305	59.8 y	NSCLC	No data available	No data available	In figure	IHC
Xu [17]	2010	China	102	60.5 y	NSCLC	No data available	No data available	5.6	IHC
Li [18]	2013	China	112	59.2 y	NSCLC	No data available	No data available	No data available	RT-PCR
Tirino [19]	2009	Italy	89	No data available	NSCLC	No data available	No data available	No data available	IHC
Huang [20]	2015	China	239	63 y	NSCLC	60.0 months	No data available	In figure	IHC
Su [21]	2015	China	159	61 y	NSCLC	62.0 months	No data available	In figure	IHC
Qiu [22]	2015	China	183	No data available	NSCLC	No data available	No data available	In figure	IHC
Roudi [23]	2015	Iran	133	67 y	NSCLC	No data available	No data available	In figure	IHC
Zheng [24]	2015	China	81	50 y	NSCLC	No data available	No data available	No data available	IHC

${}^{*}$ Early stage non-small cell lung cancer; In figure, data got from figure; qPCR, quantitative PCR; RT-PCR, reverse transcription PCR; IHC, immunohistochemistry.

2.5 The cancer genome atlas (TCGA) data for lung cancer

For mRNA expression data, TCGA genomic data for LUNG (Provisional) was retrieved. The returned value indicates the number of standard deviations away from the mean of expression in the reference population ( $z$ score). mRNA expression data ( $z$ score $=$ 2) of lung adenocarcinoma ( $n=$ 522) and lung squamous cell carcinoma ( $n=$ 504) patient samples were analyzed using cBioPortal for Cancer Genomics platform (http://www.cbioportal.org/public-portal/). The prognostic value of the CD133 gene in lung cancer was analyzed using Kaplan-Meier Plotter (http://kmplot.com/analysis/). We focused our analysis on overall survival patient information. Two patient groups (higher and lower expression levels) were compared using a Kaplan-Meier survival plot. The hazard ratio with 95% confidence intervals and log rank P value was calculated.

2.6 Meta-analysis

We identified relevant published research articles by a systematic search of the following electronic databases: Medline (1948 to December, 2015), EMBASE Classic $+$ EMBASE (1947 to December, 2015), and The Cochrane Central Register of Controlled Trials. The following terms were used to search English language articles and abstracts: (“CD133” OR “prominin-1”) AND (“lung neoplasm” OR “lung carcinoma” OR “lung cancer”). The search also was guided by a thorough examination of reference lists of original and review articles, relevant books, and meeting abstracts. Abstracts were initially checked for relevance and the full article was retrieved for all potentially eligible studies. We judged publications to be relevant if they met the following criteria: (1) studies of CD133 expression based on primary lung cancer tissue (via either surgical or biopsy); (2) diagnosis of lung cancer was proven by histopathological methods; (3) inclusion of sufficient data to allow the estimation of an odds ratio (OR) with a 95% confidence interval (95% CI); (4) letters to the editor, case report studies, and reviews were excluded. The eligibility criteria were assessed by two independent investigators (Wen and Wang). Any disagreement within or between pairs was resolved by discussion. All data were independently abstracted by two reviewers (Hou and Xia). Disagreements in data extraction were resolved by consensus, referring back to the original article. Data tables were made to extract all relevant data from texts, tables and figures of each included studies, including author, year, country, patient number, detection method, cancer type, as well as the expression-related survival. In case the prognosis was plotted as a Kaplan-Meier curve in some articles, the software GetData Graph Digitizer 2.24 (http://getdata-graph-digitizer.com/) was applied to digitize and extract the data.

2.7 Statistical analysis

Chi-square tests were performed to verify the association between CD133 expression and the clinical and pathologic features of NSCLC. The statistical analyses and graphics were performed with GraphPad Prism 5. OR with 95% confidence intervals (CIs) was calculated by using Review Manager Version 5.3 for Windows (Cochrane Collaboration, http://www.cc-ims.net/RevMan). Fixed or Random model was used depending on heterogeneity analysis. P value $<$ 0.05 was considered as statistical significance. In addition, if sufficient studies were included, we intended to construct a funnel plot of all studies to investigate the likelihood of publication bias.

Figure 3.

Flow diagram of identifying potential studies in our meta-analysis.

Figure 4.

Meta-analysis of CD133 and the clinical characteristics of patients with NSCLC.

Figure 5.

Meta-analysis of CD133 and the clinical characteristics of patients with early stage NSCLC.

Figure 6.

Meta-analysis of correlation between CD133 and overall survival.

Figure 7.

Funnel plot for publication bias test (CD133 and NSCLC).

3. Results

RT-PCR analysis was performed in order to determine the level of CD133 mRNA in lung cancer specimens. CD133 mRNA in cancer tissue was significantly higher than that in normal tissue ( $P<$ 0.05, Fig. 1A). Western blot analysis was showed that CD133 expression was also increased in cancer tissue ( $P<$ 0.05, Fig. 1B). Results show that the level of CD133 mRNA was coincident with the level of protein expression (Fig. 1A and B). Immunohistochemical staining was performed in order to determine the level and localization of CD133 protein. CD133 was found not only in the membranous localization of the cancer cells, but also in the cytoplasmic localization (Fig. 1C). We then analyzed the potential relationship between the expression of CD133 and the clinicopathological characteristics of these patients. CD133 was associated with differentiation, lymphatic invasion, venous invasion of NSCLC ( $P<$ 0.01, Table 1). CD133-negative expressers showed a significantly longer 5-year survival rate than CD133-positive ones by using the Kaplan-Meier method ( $P=$ 0.029, Fig. 1D).

3.1 CD133 mRNA in different lung cancer subtypes

To determine whether CD133 mRNA is associated with a specific subtype of lung cancer, we compared the mRNA levels of CD133 in lung adenocarcinoma and lung squamous cell carcinoma specimens. We found that the mRNA level of CD133 were higher in T4 lung adenocarcinoma, whereas no difference in T1-T4 stages of lung squamous cell carcinoma (Fig. 2A). CD133 mRNA was highly expressed in M1 lung adenocarcinoma and less expressed in M1 lung squamous cell carcinoma compared with their matched M0 tissues (Fig. 2B). Interestingly, we found that CD133 mRNA expression could be a good indicator for lung adenocarcinoma by using both cBioPortal (Fig. 2C) and Kaplan-Meier plotter analysis (Fig. 2D). Taken together, these data indicate that CD133 may play different roles in different subtypes of lung cancer.

3.2 Meta-analysis results

Detailed search steps were described in Fig. 3. One hundred and forty-six articles were identified initially using the search strategy above. One hundred and eighteen articles included those on tumors other than lung cancer. Twelve of residual 28 papers were excluded due to nonhuman experiments, non-lung-related studies, review, or letter to editor, through reading title and abstract. After further screening, the report by Hilbe et al. [12] was excluded due to CD133 expression was detected in endothelial progenitor cells but not in tumor cells. The studies of Le et al. [7], Janikova et al. [13] and Pirozzi et al. [14] provided a hazard ratio of overall survival (OS) or disease-free survival (DSF) but insufficient information on the clinicopathological parameters of the patients. Two reports provided the information on CD133 expression and early stage NSCLC [8, 15]. Eleven studies focused on CD133 expression and NSCLC were included [9, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24]. Eventually, 11 eligible studies were included in the present meta-analysis and listed in Table 2.

There was no clear correlation between CD133 expression and age (pooled OR $=$ 1.08, 95% CI: 0.87–1.34, $P=$ 0.47) (Fig. 4A), sex (pooled OR $=$ 1.00, 95% CI: 0.79–1.27, $P=$ 0.98) (Fig. 4B), and histology (pooled OR $=$ 1.04, 95% CI: 0.82–1.31, $P=$ 0.78) (Fig. 4C). However, CD133 expression was associated with differentiation of NSCLC (pooled OR $=$ 1.98, 95% CI: 1.50–2.62, $P<$ 0.00001) (Fig. 4D). Furthermore, we found that CD133 was related with histology of early stage NSCLC (pooled OR $=$ 0.40, 95% CI: 0.23–0.67, $P=$ 0.0006) (Fig. 5), but not with sex (pooled OR $=$ 1.18, 95% CI: 0.70–1.98, $P=$ 0.53) (Fig. 5). CD133 expression was statistically significantly associated with a poor OS rate of NSCLC patients (pooled HR $=$ 1.95, 95% CI: 1.36–2.79, $P=$ 0.0003) (Fig. 6A), but not with DFS rate (data were not shown). The presence of CD133 was not related to OS of the patients with early stage NSCLC (pooled HR $=$ 2.16, 95% CI: 0.16–28.93, $P=$ 0.56) (Fig. 6B). No obvious publication bias was observed in these studies (Fig. 7).

4. Discussion

To our knowledge, this is an updated meta-analysis to systematically evaluate the relationship between CD133 and NSCLC. In the studies of Mizugaki et al. [9] and Li et al. [18], they didn’t find any relationships between CD133 and differentiation of NSCLC. However, both Wu et al. [16] and Xu et al. [17] found CD133 was related to tumor cell differentiation degree. Our pooled result showed that CD133 expression was associated with differentiation of NSCLC. Included studies in this meta-analysis were not found any associations of CD133 with age and sex [9, 10, 16, 17, 18, 19, 20, 21, 22, 23, 24]. Consistent with the results of each individual study, our pooled results also confirmed that CD133 was not related to age and sex. Two papers showed that CD133 was related with histology of early stage NSCLC [8, 15]. In this meta-analysis, we compared the impact of CD133 on squamous cell carcinoma (SCC) with adenocarcinoma (ADC). Our pooled results confirmed that CD133 expression was only related with histology of early stage NSCLC. Interesting, no associations were found between CD133 and histology of all stage NSCLC. CD133 has prognostic significance for patients with colorectal cancer [25], hepatocellular carcinoma [26], and gastric cancer [27]. In our study, we evaluated the expression of CD133 and its prognostic value for the patients with NSCLC. DFS was calculated as survival without relapse or death from the date of first complete remission, censoring patients alive in continuous complete remission at the last follow-up date [28]. Our pooled results found CD133 expression had significant impact on the OS of the patients with NSCLC but not on DFS. These results indicated that CD113 may be used as a prognostic marker for NSCLC. However, according to current data, it not a prognostic marker for early stage NSCLC. In accordance with some other types of malignancies, CD133 expressed NSCLC patients had a lower OS by comparing to negative ones [25, 26, 27].

The cause of inconsistent results in each individual study was very complex. Several reasons may influence the conclusion of each included report. For example, the antibody that used to detect CD133 in each study has no universal standard. As noted in the introduction, CD133 is a transmembrane glycoprotein. Minor changes in glycan structure could have drastic functional implications both at the protein and at the cellular levels [29]. Other limitations in each individual study should be considered, such as the different cutoff value of immunohistochemical staining in each study. Although we can’t regulate these limitations in individual study, certain limitations in our meta-analysis need to be pointed out. First, the numbers of published studies were still not sufficiently large for the analysis of the CD133 expression and NSCLC. Second, language restriction could introduce bias in the results of the meta-analysis [30]. Finally, lack of the original data of the reviewed studies limited our further evaluation.

Interestingly, consistent with the pooled results from previous studies, our results in this study also confirmed that CD133 was associated with differentiation of NSCLC and the survival rate of NSCLC patients. In our study, we found CD133 is mainly localized in the membrane and cytoplasm in NSCLC cells. As noted in above, CD133 is known as a surface protein, however, anomalous localization in the nucleus has been described in various malignancies [20, 31, 32]. Nuclear localization of CD133 may be an indicator of poor prognosis in non-small cell lung cancer [20]. We didn’t find nuclear localization of CD133 in our specimens and we will collect more NSCLC tissues for further study.

In summary, this present study shows a significant correlation between CD133 expression and differentiation of NSCLC both in our results and pooled previous results. CD133 may have prognostic significance for patients with NSCLC based on currently obtained data. The value of the current meta-analysis compensates for the individual lack of precision of most studies, a problem alleviated by pooling. Further studies are required to evaluate CD133 potential use in predicting patients’ outcome.

Footnotes

Acknowledgments

This study was supported by National Natural Scientific Foundation of China (No. 81502558) and Talents Introduction Projects of Liaoning Medical University. We are grateful to Liu for providing their paper to us.

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

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The roles of CD133 expression in the patients with non-small cell lung cancer

Abstract

BACKGROUND:

METHODS:

RESULTS AND CONCLUSION:

Keywords

1. Introduction

2.1 Subjects

2.2 RT-PCR

Table 1 Relationship between CD133 and the clinicopathological parameters of patients with NSCLC

2.4 Immunohistochemical studies (IHC)

2.6 Meta-analysis

2.7 Statistical analysis

3.1 CD133 mRNA in different lung cancer subtypes

3.2 Meta-analysis results

4. Discussion

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Relationship between CD133 and the clinicopathological parameters of patients with NSCLC