EMERGING ROLE OF CXCL8 IN SQUAMOUS CELL LUNG CARCINOMA · squamous cell lung cancer and to clarify the relationship of these markers to each other and with classical clinicopathological

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269

The Egyptian Journal of Biochemistry & Molecular Biology VOL 30 (N.2)269- 282 Dec. 2012

EMERGING ROLE OF CXCL8 IN SQUAMOUS CELL LUNG

CARCINOMA

*Manal Louis Louka1, Enas Samir Nabih

1, Hala Fawzy Mohamed

Kamel1 , Fayda Ibrahim Abdel Motaleb

1, Mohamed Ali El Sayed

2

Departments of 1Medical Biochemistry and

2Chest Diseases, Faculty

of Medicine, Ain Shams University, Cairo, Egypt

Received 12/9/2012– Accepted 31/10/2012

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ABSTRACT

Lung cancer is the leading cause of cancer-related death in

industrialized countries. CXCL8 is a cytokine that has been shown to

exert effects relevant to cancer growth and progression. There are few

reports on the clinical roles of CXCL8 in lung cancer progression. The

aim of our study was to evaluate the serum levels of CXCL8 and the

tissue expression of Bcl-2 and p53 in squamous cell lung cancer

patients in order to explore the possible diagnostic role of CXCL8 in

squamous cell lung cancer and to clarify the relationship of these

markers to each other and with classical clinicopathological factors.

Serum and tissue samples were obtained from 50 patients who

underwent fibreoptic bronchoscopy for squamous cell lung carcinoma.

The tissue expression of both Bcl-2 and p53 proteins in the malignant

and control groups were evaluated by ELISA and Western blot. Serum

levels of CXCL8 were measured by ELISA. They showed significant

increase in the malignant group versus the control group. Regarding

the different clinicopathological factors, serum CXCL8 showed

significant increase with the histological grades and stages. While no

statistical difference was found in the median levels of Bcl-2, p53 as

regards the different stages and only p53 showed statistical difference

as regards the different histological grades. Concerning the levels of

the three investigated biomarkers to each other, p53 and CXCL8 were

the only biomarkers that demonstrated a significant correlation.

CXCL8 also showed higher sensitivity and specificity in comparison

to the other parameters.

Key words: Lung cancer, Apoptosis, CXCL8, p53, Bcl-2.

Manal Louis Louka et al.


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270

INTRODUCTION

Lung cancer accounts for one-third of all cancer-related deaths

worldwide, approximately 1.2 million new cases per year. According

to statistics released by the National Cancer Institute, lung cancer

cases in Egypt represent 8.2 percent of total cancer cases in men and

about 2.4 percent of total cases among women (Ramzy et al., 2011).

Interleukin-8/CXCL8 (IL-8) is a member of the CXC chemokine

family, which was originally classified as a neutrophil chemoattractant

with inflammatory activity. It is a potent angiogenic factor in several

cancers including non-small cell lung cancer (NSCLC) and is

associated with metastasis. CXCL8 has been shown to be an important

mitogenic factor in a variety of cancers and is involved in the

pathogenesis of endometriosis by up-regulating proliferation and

growth and restricting apoptosis in Embryonic Stem Cells by

activating the PTEN/Akt pathway and mediating the expression of

survivin and Bcl-2 (Li et al., 2012). The role of CXCL8 in lung

cancer has not been fully defined (Zhu et al., 2004).

Bcl-2 family proteins have been studied intensively owing to their

importance in the regulation of apoptosis, tumorigenesis and cellular

responses to anti-cancer therapy (Richard and Andreas, 2008).

Several studies have also been done on the p53 tumor suppressor

protein. It is often referred to as the "guardian of the genome" since its

response to DNA-damage or checkpoint failure gives rise to a series

of anti-proliferative responses. One of the most important functions of

p53 is its ability to induce apoptosis, while disruption of this route can

promote tumor progression and chemo resistance (Meulmeester and

Jochemsen, 2008). Mutations in the p53 tumor suppressor gene are

well-known molecular events in human malignancy. Cells with a

mutated p53 gene resulting in functionally inactive p53 protein cannot

control genomic integrity and tend to escape from apoptosis, leading

to the development of malignancy (Soussi, 2000).

The aim of our study was to explore the possible role of CXCL8 as an

antiapoptotic marker in squamous cell lung cancer via the expression

of Bcl-2 and p53. Moreover, to evaluate the clinical significance of

these markers, their diagnostic utility and their predicting ability with

respect to the different clinicopathological parameters.

EMERGING ROLE OF CXCL8 IN SQUAMOUS ……..


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271

MATERIALS AND METHODS

Patients and Tissue Samples

The studied groups included 50 squamous cell lung cancer patients

and 20 control subjects. Tissue samples were obtained from 50

patients (Thirty eight were males and twelve were females) who

underwent fiberoptic bronchoscopy for primary tumors in Ain Shams

Hospitals in Cairo from September 2010 to May 2011. Their ages

ranged from 47 to 75 years old (60±8.5). Biopsies from lung tissues of

20 sex and age matched nonsmoker adults ranging from 48 to 76 years

old (62±8) were also collected and acted as the control. The control

subjects presented with hemoptysis (n=10), chronic persistant cough

(n=6) with no obvious evident explanations, foreign body aspiration

(n=2) and 2 subjects presented with postoperative lobe or segmental

atelectasis (therapeutic bronchoscope). Informed consent was signed

by all participants in this study.

The histological type for all patients was squamous cell lung

carcinoma. Patients received no other forms of therapy before

bronchoscopy. Specimens were fixed in 10% formalin solution for

histological examination. At the time of bronchoscopy, tissue samples

were promptly dipped in liquid nitrogen and stored frozen at -80°C

until use for tissue expression of both Bcl-2 and p53 proteins. Lung

cancer was staged using a widely used classification system and

graded by the Nottingham grading system (Mountain, 1997).

Blood samples were collected from all participants and were

centrifuged at 14,000g for 10 minutes. Serum was separated and

frozen at _80ºC until further assay for CXCL8 by ELISA.

Evaluation of Bcl-2, p53 protein in lung tissues by ELISA

The levels of the Bcl-2 and p53 proteins in the control and malignant

lung tissue lysates were determined by ELISA (BioSource

International, Inc., Camarillo, California, USA).

Briefly, the tissues were thawed on ice followed by extraction of

proteins with an extraction buffer composed of (50 mM Tris, pH 7.4,

250 mM NaCl, 5 mM EDTA, 50 mM NaF, 1 mM Na3VO4, 1%

Nonidet P40 [Roche Applied Science, Germany], 1 mM PMSF [stock

is 0.1 M in DMSO] and then protease inhibitor cocktail [Sigma, St.

Louis, USA] was added. After centrifugation, the supernatant was

frozen at -80ºC until further use. The protein concentration was




272

determined using the Bradford assay (Bio-Rad, Richmond, CA) using

bovine serum albumin as the calibrator (Bradford et al., 1976).

Detection of mutant p53 and Bcl-2 in lung tissues by Western Blot

(WB) technique

WBs were performed according to (Sambrook et al., 1989) and

adapted by Eissa and Seada, (1999) as follows: Sixty micrograms of

cell lysate proteins in loading buffer (50 mmol/L Tris, 20 g/L sodium

dodecyl sulfate, 100 mL/L glycerol, 100 mmol/L dithiothreitol, pH

6.8) were boiled for 3 min and separated by 12% sodium dodecyl

sulfate-polyacrylamide gel electrophoresis. The gels were transblotted

to nitrocellulose filters in Tris-glycine buffer (25 mmol/L Tris, 192

mmol/L glycine, 200 ml/L methanol, pH 7.4) for 5 h at 60 V. The

nitrocellulose sheets were washed, and unoccupied binding sites were

saturated with 50 g/L bovine serum albumin in Tris-buffered saline

buffer (50 mmol/L Tris, pH 7.5, 150 mmol/L NaCl, 2 mmol/L EDTA,

1 ml/L NP-40) for 1 h at room temperature. Then the filters were

sequentially incubated with phosphate-buffered saline supplemented

with 10 g/L bovine serum albumin and a mouse monoclonal anti-Bcl-

2 antibody and anti p53 antibody (Abcam, Cambridge, MA, USA)

diluted 1:1000 (by volume) overnight at 4 °C, then with rabbit anti-

mouse IgG alkaline phosphatase conjugate (Abcam, Cambridge, MA,

USA) diluted 1:500 (by volume) for 90 min at room temperature.

Each of these steps was separated by 3–5 min washes in phosphate

buffered saline, containing 3ml/L Tween 20. Finally, the filters were

incubated with alkaline phosphatase substrate solution (1 mL of

substrate buffer, containing 100 mmol/L NaCl, 5 mmol/L MgCl2, 100

mmol/L Tris, pH 9.5, with 4 ml of nitro blue tetrazolium and 4 mL of

5-bromo-4-chloro-3-indolyl phosphate) at room temperature until the

developed bands were of the desired intensity, then the reaction was

stopped by 200 ml of 0.5 mol/L EDTA (pH 8) and 50 ml of

phosphate-buffered saline.The molecular weight of the protein bands

was calculated by comparison with the mobilities of the standard

proteins (Abcam, Cambridge, MA, USA).

Evaluation of serum CXCL8 by ELISA

Serum CXCL8 was measured in both the malignant and the control

groups using Human CXCL8/IL-8 Immunoassay (Quantikine, R&D

Systems, Minneapolis, USA) according to the manufacturer´s

instructions.




273

STATISTICAL ANALYSIS

The analysis was done using the Statistical Package for the Social

Sciences (SPSS software version 19). Data are expressed as

mean±standard deviation (S.D.). Using the Non Parametric test (Mann

Whitney test and/or Kruskal-Wallis (χ2) test), the mean rank and

median values of the different studied parameters were estimated and

their significances in different types were determined. They were also

related to the clinicopathological parameters using ANOVA test.

Correlation between different variables was performed by pearson

correlation. For the above comparisons, p<0.05 was considered

statistically significant. Receiver operating characteristic (ROC) curve

determined the threshold value for optimal sensitivity and specificity,

which was constructed by calculating the true positive fraction

(sensitivity percent) and false positive fraction (100-specificity) of

markers at several cut off points.

RESULTS

This study included 50 malignant squamous cell carcinoma and 20

lung tissues specimens from non smoker control adults and their

clinicopathological factors are shown in table 1.

Clinical sample analysis

Bcl-2 and p53 concentrations were measured by ELISA in the

malignant and control lung tissue lysates (table 2 and 3). In the control

tissue samples, Bcl-2 values ranged from 1.7-64.8 ng/mg protein

(mean rank, 26.17) and p53 values ranged from 0.7-10.5 ng/mg

protein (mean rank, 28.13). Regarding the tissues obtained from

squamous cell lung carcinoma, Bcl-2 values ranged from 3.3-325.7

ng/mg protein (mean rank: 42.31, p<0.05 versus control group) and

p53 values ranged from 1.4-18.2 ng/mg protein (mean rank: 41.35,

p<0.05 versus control group).

The median levels of tissue Bcl-2 and p53 increased significantly in

the malignant group (Bcl-2: 35.6, p53: 6.8) versus the control group

(Bcl-2: 17.4, p53: 3.8, p<0.05, p<0.05 respectively). Similarly, the

mean serum CXCL8 increased significantly in the malignant group

(205.8±102.26 pg/ml) versus the control group (68.68 ±18.7 pg/ml,

p<0.05) table 2 and 3.

Cut-off points for p53, Bcl-2 protein and CXCL8

Optimal cut-off points for p53, Bcl-2 protein and CXCL8 were




274

(10.05 ng/mg protein, 53.45 ng/mg protein and 102.5 pg/ml

respectively). The best cut-off values were estimated to maximize the

sum of sensitivity and specificity (table 4).

Comparison of Bcl-2 and p53 expression by WB and ELISA

Seventy specimens were analyzed by both WB and ELISA, 75.7%

and 74.28% of these specimens showed agreement between the two

methods for Bcl-2 and p53 expression respectively(Table 5,6 and

fig. 1).

The relation between investigated molecular markers and

clinicopathological factors

The levels of the three investigated molecular markers in relation to

clinicopathological factors are shown in table 7. There was no

significant relation between Bcl-2, p53 and CXCL8 as regards the

smoking status (p>0.05). There was no significant relation between

Bcl-2 and the different histological grades. In the contrary, p53 and

CXCL8 showed significant increase with the different histological

grades (p<0.05). Both Bcl-2 and p53 exhibited no significant relation

with the clinical stages (p>0.05). While, CXCL8 showed a significant

increase regarding the clinical stages (p<0.05).

Correlation between the different investigated biomarkers

Concerning the levels of the three investigated biomarkers to each

other, p53 and CXCL8 were the only biomarkers that demonstrated a

significant correlation with each other (r=0.384) (Table 8).




275

Table (1): Clinicopathological factors in the different studied groups

Table (2): Levels of investigated parameters in the malignant group as

compared to the control group

Groups Bcl-2

(ng/mg)

p53

(ng/mg)

Control Group

Median

Mean Rank

Range

17.4

26.17

1.7-64.8

3.8

28.13

0.7-10.5

Malignant Group

Median

Mean Rank

Range

35.6

42.31*

3.3-325.7

6.8

41.35*

1.4-18.2

*p<0.05 versus control group.

Clinicopathological factors Control

No. (%)

Malignant

No. (%)

Male

Female

12 (60%)

8 (40%)

38 (76%)

12 (24%)

Non Smoker

Smoker

----

24 (48%)

26 (52%)

Affected Lung:

Right Lung

Left Lung

----

32 (64%)

18 (36%)

Affected Lobe:

Upper Lobe

Middle Lobe

Lower Lobe

----

32 (64%)

12 (24%)

6 (12%)

Grades

Grade 1

Grade 2

Grade 3

----

8 (16%)

33 (66%)

9 (18%)

Stages

Stage I

Stage II

Stage III

----

18 (36%)

14 (28%)

18 (36%)

Tumor size

<3cm

>3cm

----

31 (62%)

19 (38%)




276

Table (3): Serum levels of CXCL8 in the malignant group compared

to the control group

Parameter Control Group

(mean±SD)

Malignant Group

(mean±SD)

CXCL8 (pg/ml) 68.68±18.7 205.8±102.26*

*p<0.05 versus control group

Table (4): Sensitivity and specificity of different investigated

parameters by using Receiver operating characteristic (ROC) curve.

Table 5: Comparison of Bcl-2 expression in tissue lysates by WB and

ELISA.

Western blot

Bcl-2

ELISA Positive Negative

Tumor Control Tumor Control

Positive 27 0 1 1

Negative 15 0 7 19

Seventy specimens were analyzed by both WB and ELISA. Fifty three

of 70 (75.7%) of these specimens showed agreement between the two

methods.

Variables Cut-off Sensitivity Specificity

Area

under

ROC

curve

Bcl-2

(ng/mg) 53.45 56% 95.8% 0.825

p53

(ng/mg) 10.05 55.6% 95.5% 0.86

CXCL8

(pg/ml) 102.5 84% 97.1% 0.964




277

Table 6: Comparison of p53 expression in tissue lysates by WB and

ELISA.

Western blot

p53

ELISA

Positive Negative

Tumor Control Tumor Control

Positive 26 0 2 1

Negative 15 0 7 19

Seventy specimens were analyzed by both WB and ELISA. Fifty two

of 70 (74.3%) of these specimens showed agreement between the two

methods.

Table (7): Relation between levels of studied parameters and

clinicopathological factors

Factors

Bcl-2 p53 CXCL8

Media

n

Positivity

Rate Median

Positivity

Rate Mean±SD

Positivity

Rate

Non Smoker

(n=24)

Smoker(n=26)

34.1

39.9

11 (45.8%)

16 (61.5%)

6.7

6.8

9(37.5%)

9(34.6%)

214.1±106.2

203.9±89.4

18 (75%)

25 (96.2%)

Grade 1 (n=8)

Grade 2(n=33)

Grade 3 (n=9)

37

31.3

73

3(37.5%)

12(36.4%)

5(55.6%)

2.85

6.7

13.1

1(12.5%)

10(30.3%)

7 (77.8%)

144.9 ±72.6

197.9±86

311±95.1

5 (62.5%)

28 (84.8%)

9 (100%)

p<0.05* p<0.05*

Stage I (n=18)

Stage II(n=14)

Stage II(n=18)

31

35.6

77.4

6(33.3%)

7(50%)

6(33.3%)

5.15

7

7.59

7(38.9%)

5(35.7%)

7(38.9%)

168.25±87.7

204.9±105.8

256±92.5

14(77.8%)

10(71.4%)

18(100%)

p<0.05*

*p<0.05: is significant.




278

Table (8): Correlation between the investigated biomarkers

Bcl-2 p53 CXCL8

Bcl-2 ------ 0.133 0.194

p53 0.133 ------ 0.384*

*p< 0.05 level (2-tailed).

Figure 1: WB analysis of Bcl-2 and mutant p53 expression in lung

cancer tissues.

Lane 1, molecular weight standards. Lanes 2-10 corresponds to the

malignant samples. They all showed a single band of 24 kDa and 26

kDa, which corresponds to the molecular mass of mutant p53 and Bcl-

2 protein respectively.

DISCUSSION

There are few reports on the clinical roles of CXCL8 in lung cancer

progression. Although CXCL8 was suggested as one of the important

angiogenic factors in non–small cell lung cancer, its role in lung

cancer has been controversial. Therefore, serum CXCL8 levels in

squamous cell lung cancer patients and healthy age-matched subjects




279

were examined by ELISA in our study.

The mean serum CXCL8 increased significantly in the malignant

group (205.8±102.26 pg/ml) versus the control group (68.68±18.7

pg/ml, p<0.05) and it showed significant increase as regards the

different histological grades and stages (p<0.05, p<0.05 respectively).

This was in agreement with previous reports (Orditura et al., 2002,

Cai et al., 2009 and Enewold et al., 2009). Cai et al. (2009) reported

that CXCL8 levels were significantly elevated in patients with

localized lung cancer (206.33±55.87) compared with those in healthy

donors (79.25±23.08) and also was significantly increased in lung

cancer patients with bone metastases (392.29±134.23) compared with

those in patients with localized cancer (206.33±55.87, p<0.05).

Additionally, CXCL8 was reported to be produced by NSCLC lines

(Po˜ld et al., 2004; Zhu et al., 2004 and Baird et al., 2011). No

significant difference in its levels was found regarding the smoking

status.

Bcl-2 and p53 proteins are both related to apoptosis and thus their

relationship is of interest. In this study, the results showed that Bcl-2

and p53 were detected by both ELISA and western blot techniques in

the lung cancer tissues. They showed significant increase in their

median values in the malignant group versus the control group by

ELISA (p<0.05, p<0.05 respectively).This was in agreement with

previous reports (Pappot et al., 1996, Tas et al., 2006).

By comparison of Bcl-2 and p53 expression by WB and ELISA,

75.7% and 74.28% of these specimens showed agreement between the

two methods respectively.

In our study, no statistical difference was found in the median levels

of Bcl-2, p53 as regards smoking status and stages which was in

agreement with Laudanski et al., (2001). On the other hand, the

median levels of p53 in our study showed significant increase as

regards the different histological grades (p<0.05).

Concerning the levels of the three investigated biomarkers to each

other, p53 and CXCL8 were the only biomarkers that demonstrated a

significant positive correlation (p<0.05).

Conclusion: Our findings suggested that all three markers are useful

for the diagnosis of squamous cell lung carcinoma; however, CXCL8 was the only marker that increased significantly with the different

histological grades and stages of patients. It also showed higher

sensitivity and specificity in relation to the other parameters. This can




280

indicate that CXCL8 could be a potential noninvasive good marker for

squamous cell lung carcinoma and the combined use of these three

markers may provide additional information for prognosis. This study

may also predict that CXCL8 had an anti-apoptotic effect on lung

cancer witnessed by the elevation of the levels of Bcl-2 and mutant

p53. Further studies on a large cohort of patients and other types of

lung cancer will be necessary to confirm these findings.

Competing interests: The authors have no conflicting interests,

including any financial, personal or other relationships with other

people or organizations, and are not supported or funded by any

company.

Acknowledgement: This work was supported by Assistant Pof. Dr.

Riham Abou Zeid, Department of Patholoy, Faculty of Medicine, Ain

Shams University.

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الملخص العربى

ئةفى تشخيص سرطان الخ+يا الحرشفية للر CXCL8 دور

، فايدة ابراھيم عبد ١، ھالة فوزي محمد كامل١، إيناس سمير نبيه١منال لويس لوقا، محمد على السيد١المطلب

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قسم الكيمياء الحيوية الطبية كلية الطب جامعة عين شمس١ قسم ا=مراض الصدرية كلية الطب جامعة عين شمس ٢

من ثم تم عمل . ة الى الوفاة فى الدول الصناعيةٳن سرطان الرئة من أكثر السرطانات المؤديفى p53 و Bcl-2 فى الدم و تعبير ا=نسجة CXCL8 ھذا البحث لتقييم مستويات

أوضحت النتائج أن ھناك زيادة معنوية لنسبة . للرئة الحرشفية مريض بسرطان الخ]يا ٥٠CXCL8 و Bcl-2 و p53 د أيضا زيادة معنوية فى مرضى سرطان الرئة كما أنه يوج

بالدم فى درجات و مراحل الورم المتقدمة مقارنة بدرجات و مراحل الورم CXCL8لنسبةزيادة معنوية فى مراحل الورم p53 و Bcl-2 على العكس لم يظھر كل من. ا=ولية

يبين ھذا البحث أنه . ى درجات الورم المختلفةزيادة معنوية ف p53 المختلفة بينما أظھر فقطبالدم كدqلة أورام غير ھجومية لتشخيص سرطان CXCL8 يمكن استخدام قياس مستوى

. للرئة الحرشفية الخ]يا

Documents

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