Research ArticleClinical Studies

Clinicopathological Significance of Sip1-associated Epithelial Mesenchymal Transition in Non-small Cell Lung Cancer Progression

NAOKO MIURA, TOKUJIRO YANO, FUMIHIRO SHOJI, DAIGO KAWANO, TOMOYOSHI TAKENAKA, KENSAKU ITO, YOSUKE MORODOMI, ICHIRO YOSHINO and YOSHIHIKO MAEHARA
Anticancer Research October 2009, 29 (10) 4099-4106;

Abstract

Background: Epithelial-mesenchymal transition (EMT) is a key event in cancer progression. The expression of EMT-related factors in non-small cell lung cancer (NSCLC) and their impact on clinicopathological variables was examined. Patients and Methods: A total of 137 NSCLC patients who underwent surgical resections were investigated. The expression of Twist, Snail, smad-interacting protein 1 (Sip1), E-cadherin, N-cadherin, vimentin and β-catenin was detected by immunohistochemical analyses. Results: The expression of Sip1 was associated with the reduced expression of E-cadherin (p=0.04) and the positive expression of N-cadherin (p=0.04). There was no association between the expression of Twist nor Snail and the epithelial or mesenchymal markers. The expression of Sip1 correlated with advanced T status (p=0.01), tumor diameter (p=0.01) and advanced stage (p=0.01). Furthermore, the expression of Sip1 was associated with poor postoperative overall survival (p=0.02). Conclusion: The expression of Sip1 is significantly associated with tumor growth and poor prognoses in NSCLC and EMT might be activated via Sip1 expression and result in accelerated tumor growth and poor survival in NSCLC.

Lung cancer is a leading cause of cancer death worldwide with an incidence of 1.2 million per year and mortality of 1.1 million per year (1). Although a surgical resection is the best therapy for early stage disease, the postoperative prognosis is poor with an overall 5-year survival of 41.4%. Even with patients in pathological stage IA, the 5-year survival is 73% and at stage IB, it is only 54% (2). Moreover, about 40% of the patients who receive surgery demonstrate recurrence within 2 years after the resection and thereafter die of metastatic spread (3).

In recent years, epithelial-mesenchymal transition (EMT) has been shown to play an important role during the progression of cancer (4). Through EMT, cancer cells can become motile and able to invade into the stroma surrounding the initial neoplastic focus, facilitating intravasation of tumor cells into the blood or lymphatic vessels, leading to dissemination to distant sites (5). There have been several reports of the role of EMT in progression, the acquisition of invasive characters or poor prognosis of several types of cancer (4, 5).

E-Cadherin is a transmembrane glycoprotein and acts as a key molecule of cell-cell adhesion in epithelia. It is crucial for the establishment and maintenance of polarity and the structural integrity of epithelia. The extracellular domain of E-cadherin interacts with E-cadherin on adjacent cells and the intracellular domain binds directly to β-catenin. β-Catenin forms a multiprotein complex and binds to the cytoskeleton, thereby this cadherin/catenin/cytoskeleton complex maintains cell-cell adhesion, cell shape and polarity and regulates migration (5). Reduced E-cadherin and/or β-catenin expression with tumor progression has been reported in many malignancies (4, 5). The loss or reduced expression of E-cadherin or β-catenin facilitates cancer invasion and these molecules are regarded as key epithelial markers of EMT (5, 6). However, the down-regulation of epithelial markers alone is not sufficient for EMT which requires the acquisition of mesenchymal functions (4, 6). N-cadherin is also a transmembrane adhesion glycoprotein (7). Forced N-cadherin expression resulted in the down-regulation of E-cadherin expression and enhanced tumor cell motility and migration (8). Vimentin is a type-III intermediate filament normally expressed in cells of mesenchymal origin. Its expression has been reported in migratory epithelial cells involved in embryonic and organogenesis processes, wound healing and tumor invasion (9). Therefore, both N-cadherin and vimentin are also regarded as mesenchymal markers of EMT and an increase in their expression makes neoplasms acquire invasive characteristics and results in poor prognosis (7, 10). The transcription factors of E-cadherin, such as Twist, Snail and Sip1 are considered as key molecules of EMT and they have been reported to play an important role in the progression of cancer in several organs (4, 7, 11-21).

Twist is a helix-loop-helix transcription factor, regarded as one of the key molecules of EMT. Twist inhibits E-cadherin promoter activity through interaction with E-boxes (6). An association between the up-regulation of Twist and recurrence, metastases, tumor grade, invasion or poor prognosis has been reported in ovarian cancer (12), hepatocellular carcinoma (HCC) (13), prostatic cancer (14), endometrial cancer (15) and breast cancer (16).

Snail is a zinc-finger transcription factor which represses E-cadherin expression through binding E2-boxes on the E-cadherin promoter. The up-regulation of Snail correlates with tumor grade, lymph node metastases, recurrence, poor prognosis or invasion in breast cancer (16-18), esophageal cancer (19) and ovarian cancer (20).

Smad-interacting protein 1 (Sip1) is a zinc-finger transcription factor targeting the E2-box on the E-cadherin promoter and it represses E-cadherin expression. Comijn et al. have reported that conditional stable expression of Sip1 cDNA significantly down-regulated E-cadherin and reduced cell-cell aggregation in a cancer cell line (22). Bindels et al. have reported that Sip1 regulated vimentin expression in breast cancer cells and might contribute to the metastatic progression of breast cancer by unknown mechanisms (9). In oral squamous cell carcinomas, Sip1 has been shown to correlate with the loss of E-cadherin expression and histological differentiation and it was an independent prognostic factor for overall survival (21).

Evidence of a role of EMT in non-small cell lung cancer (NSCLC) progression is limited. The purpose of this study was to investigate the expression of EMT-regulatory genes, Twist, Snail and Sip1 and the possible role of these molecules in NSCLC progression.

Materials and Methods

Patients. A total of 137 NSCLC patients who underwent a surgical resection at Kyushu University Hospital between June 2000 and December 2004 were included in the current study population. Written informed consent for the comprehensive use of the pathological materials was obtained from all the patients. The pathological stage of the patients was determined based on the TNM classification of the International Union Against Cancer (UICC) (23). For TNM staging, all the patients had undergone computed tomography scans of the thorax and the upper part of the abdomen, a bone scintigram, brain magnetic resonance imaging and 18-fluoro-2-deoxyglucose positron-emission tomography.

View this table:
Table I.

Patient characteristics.

The patient profiles are summarized in Table I. This study included 52 (38.0%) women and 85 (62.0%) men, ranging in age from 36 to 84 years with a mean age of 67 years. Forty-six (34.6%) patients were never-smokers and 87 (65.4%) patients were current or former smokers. The number of patients of each pathological stage IA, IB, IIA, IIB, IIIA, IIIB and IV were 47, 36, 4, 14, 30, 4 and 2, respectively. Out of the two stage IV patients, one had a renal metastasis and the other had a pulmonary metastasis in a different lobe from the primary lesion. The median follow-up duration was 3.6 years.

Reagents and antibodies. The antibodies used were Twist (H-81; Santa Cruz Biochemisty Inc., Santa Cruz, CA, USA), Snai1 (E-18; Santa Cruz Biochemistry Inc.), Sip1 (L-20; Santa Cruz Biotechnology Inc.), E-cadherin (NCH-38, HECD-1; TaKaRa, Kyoto, Japan), N-cadherin (M3613, clone 6G111; Dako, Kyoto, Japan), vimentin (M0725, cloneV9; Dako) and β-catenin (610154; BD Biosciences, Franklin Lakes, NJ, USA). The Envision system® (Dako) was applied for Twist, E-cadherin, N-cadherin, vimentin and β-catenin, the simple stain peroxidase method (Nichirei Co. Ltd., Tokyo, Japan) and the avidin-biotin-peroxidase complex technique (Nichirei Co. Ltd.) were applied for Snail and Sip1, respectively.

Immunohistochemistry. The resected specimens were fixed in 10% formalin and embedded in paraffin and 3-μm-thick sections were prepared. The sections were stained with Twist (1:100), Snail (1:100), Sip1 (1:50), E-cadherin (1:500), N-cadherin (1:25), vimentin (1:25) and β-catenin (1:200), respectively. The deparaffinized sections were incubated in 0.03% (v/v) hydrogen peroxidase in ethanol for 30 min at room temperature to quench endogenous peroxidase activity and then incubated with the primary antibody. The secondary antibodies as supplied were applied and the chromogen was developed with the immersion of the slides in a diaminobenzidine-H2O2 substrate. The slides were counterstained in Mayer's hematoxylin, dehydrated and mounted. As a negative control, nonimmune serum was used at the same dilution instead of the primary antibodies, in every run. Positive controls were stained for each staining batch.

Immunohistochemical evaluation. The expression was independently investigated by two of the authors (N.M., F.S.) using a blind protocol design (the observers had no information on clinical outcome or any other clinicopathological data). For evaluation of the Twist and Sip1 expression, the staining intensity was scored as 0 (negative), 1 (weak), 2 (medium) and 3 (strong) and the extent of staining was scored as 0 (0%), 1 (1%-25%), 2 (26%-50%), 3 (51%-75%) or 4 (76%-100%) according to the percentage of the positive staining areas in relation to the total tumor area. The sum of the intensity and extent scores was used as the final staining score (0-7) as previously reported by others (15). Tumors having a final staining score of 4 or higher for Twist and 2 or higher for Sip1 were considered to have a positive expression. For evaluation of Snail, N-cadherin and vimentin expression, specimens that exhibited staining in ≥10% of the tumor cells were classified as positive and the others as negative. Paraffin-embedded tissues from normal liver of the homogenous immunophenotype were included as positive controls for the above antigens. For evaluation of E-cadherin and β-catenin, depending on the percentage of cancer cells that preserved membranous staining, 3 categories were established: <5% positively stained cells were classified as ‘negative’, 5-50% were classified as ‘reduced’ and >50% stained cells as ‘preserved’ as previously indicated (24). Paraffin-embedded tissues from normal colon epithelium of the homogenous immunophenotype were included as positive controls for these antigens.

Clinicopathologic analyses. The clinicopathological variables analyzed were: gender, smoking history, pathological stage, tumor diameter, lymph node metastases, pathological type, tumor differentiation, pleural invasion, vascular invasion and lymphatic permeation.

Statistical analyses. Statistical analyses were performed using Chi-square tests. The prognostic significance of Twist, Snail and Sip1 in determining survival was studied with Kaplan-Meier curves, using the log-rank test. All the statistical analyses were performed using the statistical package StatView version 5.0 (SAS Institute Inc, Cary, NC, USA). A value of p<0.05 was considered to be statistically significant.

Results

Expression of Twist, Sip1 and Snail. The typical immunohistochemical distributions of Twist, Sip1 and Snail are presented in Figure 1. Twist and Sip1 expression was detected in the cytoplasm and/or nuclei of the cancer cells, whereas Snail expression was detected only in the cytoplasm. The expression rate of Twist, Sip1 and Snail was 51.1% (70/137), 58.4% (80/137) and 15.3% (21/137), respectively.

Expression of E-cadherin, N-cadherin, vimentin and β-catenin. The representative immunohistochemical staining of E-cadherin, N-cadherin, vimentin and β-catenin is shown in Figure 2. E-cadherin and β-catenin were observed at the intercellular junctions and with partly reduced expression in the cytoplasm of some of the tumor cells. The preserved expression of E-cadherin and β-catenin was 65.7% (90/137) and 70.8% (97/137), respectively. The expression of N-cadherin was detected in 9.5% (13/137) of all the specimens, in the cell membrane. Vimentin was localized in the stromal structure of the normal or neoplastic tissue as well as the cytoplasm of the neoplastic tissue. The rate of expression of vimentin in the cytoplasm of tumor cells was 12.4% (17/137).

Relationship between Twist, Snail or Sip1 expression and E-cadherin, N-cadherin, vimentin or β-catenin expression. The association between the expression of Twist, Snail or Sip1 and that of E-cadherin, β-catenin, N-cadherin or vimentin was evaluated. Tables II and III show the association between Twist, Snail and Sip1 expression and E- and N-cadherin expression, respectively. There was no relationship between the expression of Twist or Snail and that of E-cadherin, β-catenin, N-cadherin or vimentin. The expression of Sip1 had an inverse correlation with the expression of E-cadherin (p=0.04) and a direct correlation with that of N-cadherin (p=0.04) though the expression of Sip1 had no relationship with that of either β-catenin or vimentin.

Sip1 immunoreactivity and its association with clinicopathological factors. Table IV shows the relationship between the expression of Sip1 and the clinicopathological parameters. The expression of Sip1 was correlated with advanced pathological stage and T status, tumor diameter and histological classification (p=0.011, 0.009, 0.012 and 0.001, respectively), although it had no relationship with lymphatic or vascular permeation (p=0.43 and 0.11, respectively). In the 83 cases of pathological Stage I (IA; 47, IB; 36 cases) in this cohort, there was no association between the expression of Sip1 and pathological Stage IA or IB (p=0.22).

Figure 1.
Figure 1.

Immunohistochemistry of Twist (a-d), Sip1 (e-h), and Snail (i, j) in NSCLC specimens. Staining intensity, a, e: negative (score 0); b, f: weak (score 1); c, g: medium (score 2); d, h: strong (score 3); i: negative; and j: positive expression.

Figure 2.
Figure 2.

Immunohistochemistry of E-cadherin (a, b), N-cadherin (c, d), vimentin (e, f) and β-catenin (g, h) in NSCLC specimens. Upper and lower figures show negative and positive immunoreactivity, respectively.

Prognostic value of Sip1 expression. The overall and disease-free survival curves are shown in Figure 3. The 1-, 3- and 5-year survival was 96.3, 86.5 and 83.8%, respectively, in the group with negative expression of Sip1, and 93.2, 74.1 and 62.0% in the group with positive expression of Sip1 in the surgical specimens. There was a significant decrease in the overall survival in the patients with positive expression of Sip1 (median survival time 49.9 months vs. 36.6 months; p=0.019). The disease-free survival of the patients with positive expression of Sip1 tended to be shorter than that of the patients with negative expression of Sip1 (p=0.09).

Discussion

This is the first report of Twist, Snail and Sip1 expression in relation to the clinicopathological character or prognosis of NSCLC in human specimens. The expression of Sip1, found in more than half of the samples, had an inverse correlation with the expression of E-cadherin and a direct correlation with that of N-cadherin, thus suggesting that Sip1 facilitated EMT in NSCLC. Previous reports noted that Twist, Snail and Slug, which is a transcription factor known as another key molecule of EMT, are poor prognostic factors in breast cancer (16-18); moreover, Twist and Snail expression are associated with poor outcome in ovarian cancer (12, 20). In addition, Twist expression has been reported as a key indicator of an ominous prognosis in HCC (13), prostate cancer (14) and endometrial cancer (15); that of Snail in esophageal cancer (19), and that of Sip1 in oral squamous cell carcinoma (21). In the current study, although more than half of the cases showed expression of Twist, there was no relationship with E- or N-cadherin expression. The rate of Snail expression was 15.3%, which was lower than the rate of 53% in breast cancer (17), 50% in gastric cancer (8) and 78% in pancreatic cancer (25). Though both Sip1 and Snail are known as regulators of EMT and the expression of these molecules are regarded as factors of tumor aggressiveness and poor prognosis in several types of cancer (8, 17-21, 25), Snail was not activated as much in comparison to Sip1 in this study of NSCLC. Therefore, it is conceivable that EMT is regulated by multiple molecules that show differential expression depending on the type of cancer, and Sip1 has a stronger impact on EMT in NSCLC.

View this table:
Table II.

Relationship between Twist, Snail and Sip1 expression and E-cadherin expression.

View this table:
Table III.

Relationship between Twist, Snail and Sip1 expression and Ncadherin expression.

View this table:
Table IV.

Association between Sip1 expression and clinicopathological factors in patients with NSCLC.

EMT may enable NSCLC cells to invade into the stroma surrounding the initial neoplastic focus and that suggests a relationship with lymphatic or vascular permeation and N stage. However, the association between the expression of Sip1 and the invasive characteristics of the tumor or pathological N stage was not significant in this study. The expression of Sip1 was however associated with a higher pathological T stage, tumor diameter of more than 20 mm, advanced pathological stage and poor prognosis. Several reports have demonstrated the proliferation-facilitating properties of EMT in vivo and in vitro. Natsugoe et al. reported that reduced E-cadherin expression and the expression of Snail had an association with high T status and resulted in statistically significantly poor prognosis in esophageal squamous cell carcinoma (19). Gravdal et al. found that reduced E-cadherin expression was related to increased tumor diameter and consequently a shortened time to progression, increased recurrence rate and cancer specific death in prostate cancer (10). In addition, there have been other reports that showed a tendency of an association between the large size of the tumor and EMT in hepatocellular carcinoma (26) and gastric cancer (27). Croix et al. reported that the loss of E-cadherin expression may endow tumor cells with a relative growth advantage in addition to the acquisition of invasive characteristics in vitro (28). Usami et al. showed that transfection of the Snail gene in esophageal squamous cell carcinoma diminished the expression of epithelial adhesion molecules with the promotion of cell proliferation (29). Therefore, EMT may facilitate tumor growth at the primary site and result in poor prognosis in addition to providing cancer cells with invasive characteristics. Considering the role of Sip1 as a repressor of E-cadherin, Sip1 expression potentially resulted in activated tumor proliferation via E-cadherin repression adding to the larger tumor diameters, suggesting that EMT induced tumor growth at the primary site mainly through the function of Sip1 in NSCLC.

Figure 3.
Figure 3.

The survival curves of 137 patients with NSCLC in relation to Sip1 expression. (a) Overall survival. (b) Disease-free survival.

Among the cases that were investigated, Sip1 expression was found more frequently in the squamous cell carcinoma specimens than the other histological types. There has been only one report of Sip1-associated EMT using surgical specimens. In oral squamous cell carcinomas, the expression of Sip1 was associated with reduced E-cadherin expression and was related to poor prognosis (21). Thus, EMT may function differently depending on the histological type.

In conclusion, Sip1 is up-regulated in NSCLC and thus seems to play a role in the down-regulation of E-cadherin and up-regulation of N-cadherin. In NSCLC, EMT might be activated mainly via Sip1 expression, resulting in an accelerated tumor growth and poor survival. However, further examination is necessary to clarify this mechanism.

Acknowledgements

We thank Brian Quinn for his review of this manuscript.

  • Received May 23, 2009.
  • Revision received August 13, 2009.
  • Accepted August 27, 2009.

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Clinicopathological Significance of Sip1-associated Epithelial Mesenchymal Transition in Non-small Cell Lung Cancer Progression
NAOKO MIURA, TOKUJIRO YANO, FUMIHIRO SHOJI, DAIGO KAWANO, TOMOYOSHI TAKENAKA, KENSAKU ITO, YOSUKE MORODOMI, ICHIRO YOSHINO, YOSHIHIKO MAEHARA
Anticancer Research Oct 2009, 29 (10) 4099-4106;
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