2 2014( Jgh) Javed Akhtar 第一位 if (3.627)

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G A S T R O E N T E R O L O G Y

Stathmin overexpression identies high risk for lymphaticmetastatic recurrence in p N 0 esophageal squamous cellcarcinoma patientsJaved Akhtar, Zhou Wang, Wen Peng Jiang, Ming Ming Bi and Zhi Ping Zhang

Department of Thoracic Surgery, Provincial Hospital Afliated to Shandong University, Jinan, Shandong, China

Key wordsesophageal squamous cell carcinoma,lymphatic metastatic recurrence, stathmin-1.

Accepted for publication 12 December 2013.

CorrespondenceProfessor Zhou Wang, Department ofThoracic Surgery, Provincial Hospital Afliatedto Shandong University, Jinan, Shandong250021, China. Email:[email protected]

Conict of interest: The authors declare thatthey have no competing interests.

AbstractBackground and Aim: Common patterns of the operative failure after Ivor-Lewisesophagectomy in esophageal squamous cell carcinoma (ESCC) patients are locoregionallymph node metastasis. It is clinically signicant to investigate the biological markers topredict the subset of patients who are at higher risk of lymphatic metastatic recurrence. Our

research aimed to investigate the association between the Stathmin (STMN-1) gene expres-sion and lymphatic metastatic recurrence in pN0 ESCC patients after surgery.Methods: One hundred seventy-four patients who suffered from mid-thoracic ESCC andcompletely resected with Ivor-Lewis esophagectomy were enrolled in our study. The entirepatients were restricted to pN0 ESCC. Tissue specimens were examined for STMN-1expression levels by immunohistochemistry and Western blotting methods. The correlationof STMN-1 levels with clinicopathological variables, prognosis, and metastatic potentialwas analyzed.Results: One hundred patients had STMN-1 protein overexpression (57.47%), and thepatients with overexpression were accompanied by signicantly higher rate of lymphaticmetastatic recurrence as compared with patients who had low STMN-1 expression(P = 0.003). Multivariable Cox regression analysis revealed that the STMN-1 proteinexpression and T classication were independent factors to predict the lymphatic meta-static recurrence ( P = 0.007, P = 0.000, respectively).Conclusions: Even pN0 ESCC are a potential to lymphatic metastatic recurrence.Stathmin overexpression can be used as a marker to identify those patients who are at highrisk for lymphatic metastatic recurrence in pN0 ESCC after an Ivor-Lewis esophagectomy.

Introduction

Esophageal squamous cell carcinoma (ESCC) is the leading causeof cancer death worldwide. More than half of global esophagealcancers occur in China, which is one of the areas showing thehighest incidence rate of ESCC, a major histological type of esophageal cancer. 1 Surgery is the best option for curing patients inthe early stages of this disease. It remains the superior therapeuticmodality for control in patients with locally advanced disease.Despite advances in treatment, the benets of surgical resectioncombined with chemotherapy or radiotherapy is not satisfactory.The prognosis of ESCC patients still remains poor. More than half of all ESCC patients die from tumor relapse or metastasis. Somereports show that the main reason for the failure of these opera-tions is the lymphatic metastatic recurrence. Therefore, to improvethe long-term survival rate of esophageal cancer, the key is tocontrol lymph node metastatic recurrence. According to theNational Comprehensive Cancer Network (NCCN) guidelines,patients with ESCC who undergo complete resections are not

candidates for adjuvant therapy. However, our previous studyfound that the pattern of rst recurrence was lymphatic metastasis,even in pN0 ESSC patients. 2 In our opinion, it is necessary toidentify the patients who are at high risk for lymphatic metastaticrecurrence in pN0 ESCC patients. These patients may get benetsfrom adjuvant therapy. Clinically, lymph node metastasis of theESCC patients is predictive by means of the TNM staging system,while lymph node metastasis is a strong adverse factor of lym-phatic metastatic recurrence in ESCC patients who underwentesophagectomy. Usually the probability of lymphatic metastaticrecurrence can be estimated with T descriptor but sometimes it’snot sensitive enough. Therefore it is important to search for abiological marker to predict patient survival in addition to the Tdescriptor in patients with pN0 ESCC.

Stathmin-1 (STMN-1), also known as p17, p18, p19, 19 K,metablastin, oncoprotein 18, LAP 18, and Op18, is a 19 kDacytosolic protein. Its function as an important regulatory protein of microtubule dynamics has been well characterized. 3 STMN-1likely plays an important role in cell cycle progression and cell

doi:10.1111/jgh.12498

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944 Journal of Gastroenterology and Hepatology 29 (2014) 944–950

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

mailto:[email protected]

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migration. It has been reported that STMN-1 is overexpressed inmany human malignancies, such as leukemia, lymphoma, neuro-blastoma, and ovarian, prostatic, breast, and lung cancers. 4

Our previous study showed that stathmin is overexpressed ingastric cancer, 5 and the modulation of its expression correlateswith invasion and metastasis. There are some reports that STMN-1gene expression is associated with lymph node metastasis. 6 Previ-ous research showed that stathmin expression is a predictor of survival in ESCC, 7but presently there are no reports showingwhether STMN-1 overexpression is associated with lymphaticmetastasis in ESCC.

In this study, we compared STMN-1 expression with anti-human STMN-1 polyclonal antibodies in pN0 patient samples,and investigated the relationship between the STMN-1 geneexpressions with lymph node metastasis in patients who hadundergone the Ivor-Lewis esophagectomy. We aimed to explorewhether the STMN-1 gene can predict lymphatic metastasisrecurrence or not.

Methods

Ethics statement. The study protocol was approved by theethics committee of Provincial Hospital Afliated to ShandongUniversity. All the participants provided their written informedconsent for inclusion in the data analysis and manuscript publica-tion. Data were analyzed anonymously.

Patients. From January 2002 through January 2006, the fullclinical records of 174 enrolled patients, who were part of ourstudy in the Department of Thoracic Surgery, were retrospectivelystudied.

All of the patients in this study were completely resected. Thisgroup of 174 cases included 134 males and 40, with a mean ageof 59.8 years old (clinical data are shown in Table 1). All of these patients were resected using the Ivor Lewis esophago-gastrectomy with two-eld lymph node dissection for mid-thoracic ESCC.

The inclusion criteria during this study were as follows:

1 We followed the guidelines in the 2009 The Union for Interna-tional Cancer Control (UICC) standard for mid-thoracic ESCC,Ivor-Lewis esophagogastrectomy with two-eld lymph nodedissection, to achieve complete tumor resection (R0). Patho-logical examination of the esophagus after surgery revealeda cancer-free surgical margin and a lateral margin withoutresidual foci. Average lymph node dissection was more than 12.

2 All of the patients included in the study were restaged accordingto the 2009 UICC TNM staging guidelines for esophagealcancer. Patients staged pathologically after surgery with stageI-IIA (pT1,2,3N0M0) were included.

3 Adjuvant chemotherapy was not administered prior to surgery,nor was radiotherapy administered after surgery. Recurrence of the tumor was not followed by systemic chemotherapy or radio-therapy. Patients who died perioperatively were not included inthe study. The surgical procedure was the same as was men-tioned in our previous study. 7

This study was approved by the hospital’s ethics committee, andpatient consent was obtained.

Immunohistochemistry (IHC). Formalin-xed andparafn-embedded sections were dewaxed in xylene, rehydratedthrough graded alcohol, and placed in an endogenous peroxide

Table 1 Correlations of stathmin gene expression and lymphatic metastatic recurrence with clinicopathological characteristics in esophagealsquamous cell carcinoma patients

Characteristics No. of patients STMN-1 expressionRecurrence rate P ‡n = 174 Low ( n = 74) High ( n = 100) P †

Age 0.921 0.649

< 50 37 16 21 16 (43.2%)≥ 50 137 58 79 61 (44.5%)Gender 0.712 0.110

Male 134 58 76 63 (47.0%)Female 40 16 24 14 (35.0%)

Tumor size 0.006† 0.013‡< 3 cm 58 27 31 16 (27.6%)3–5 cm 68 31 37 34 (50.0%)> 5 cm 48 16 32 27 (56.3%)

Differentiation 0.775 0.171Low 49 20 29 24 (49.0%)Mid-high 125 54 71 53 (42.4%)

T status 0.016† 0.000‡T1 12 6 6 3 (25.0%)T2 70 33 37 18 (25.7%)T3 92 35 57 56 (60.9%)

STMN-1 overexpression 0.003‡Yes 100 52 (52.0%)No 74 25 (33.8%)

†Chi-square test or χ 2 test. ‡Log–rank test.

J Akhtar et al . Stathmin expression in esophageal cancer

945Journal of Gastroenterology and Hepatology 29 (2014) 944–950




block for 10 min. Antigen retrieval was performed using micro-waves in 10 mM of citrate buffer for 15 min and processedusing immunohistochemical streptavidin peroxidase conjugatemethod. Rabbit anti-STMN-1 polyclonal antibodies were pur-chased from Abcam (Cambridge, MA, USA). As for the negativecontrol, the primary antibody was replaced by the phosphate-

buffered saline (PBS). All sections were examined by two inde-pendent pathologists who were blinded to the clinical data. Theimmunohistochemical score (IHS) was calculated by combiningthe proportion score (percentage of positive stained cells) with thestaining intensity score. The proportion score ranged from 0 to 4,as follows: 0 ( < 5%), 1 (5–24%), 2 (25–49%), 3 (50–74%), and4 (≥ 75%). The staining intensity was scored as follows: 0 (nega-tive), 1(weak), 2 (moderate), and 3(strong). The proportion scoreand staining intensities score were then multiplied to generatethe IHS for each case. The case with IHS ≥ 4 was considered to bepositive expression (same as our previous study). 7

Protein extraction and Western blotting. We pre-pared tissue extracts in RIPA lysis buffer (25 mM Tris pH 7.5, 1%

Triton X-100, 0.5% sodium deoxycholate, 5 mM EDTA, 150 mMNaCl) containing a cocktail of protease inhibitors (Sigma, St.Louis, MO, USA). Protein concentrations were determined usingthe Bradford method.The Bio-Rad protein assay reagent (Bio-Rad,Bio-Rad Laboratories, Richmond, CA, USA) and 20–40 mg of proteinmixed with loading bufferwas loaded per lane, separated by12% sodium dodecylsulfate -polyacrylamide gel electrophoresis(SDS-PAGE). Proteins were transferred to polyvinylidene uoride(PVDF) membrane lters (Millipore, Billerica, MA, USA). Non-specicbinding wasblocked by incubation in PBScontaining 0.1%Tween 20 (PBS-T) and 5% skim milk. PVDF membranes wereblocked with 5% dry milk for 1 h at 4°C. Membranes wereincubated in STMN-1 primary antibody (1:1000) overnight at4°C. The membranes were then incubated with the correspondingsecondary antibody (1:2000, horseradish peroxidase-conjugatedanti-rabbit) in TBST-5% nonfat milk for 1 h at room temperature,and the immunoreactive bands were visualized using EZ ECLChemiluminescence Detection Kit for HRP (Biological IndustriesLtd, Kibbutz Beit Haemek, Israel). Images were acquired usingthe LAS3000 Imager (Fujilm, Fuji, Edison, NJ, USA).Membranes were reprobed for beta-actin as a loading control.

Follow-up after surgery and the diagnosis of lymph node metastasis. After surgery, patients were regu-larly reexamined every 3–6 months. The checkup included a thor-ough physical examination, chest and upper abdomen computedtomography scan, and abdominal ultrasound. Some of the patients

underwent Positron Emission Tomography and Computed Tomog-raphy (PET-CT) scan examination. We compared the PET-CTexamination with preoperative imaging data; if there was progres-sive lymph node enlargement; we used the clinical basis to diag-nose lymphatic metastatic recurrence. Some patients’ diagnoseswere based on biopsies. If new lesions appeared in the otherorgans, we excluded the primary tumor and clinically diagnosedthem as metastatic cancers. The study follow-up ended in January2011; the longest follow-up period was 6 years, an average of 48.4 ± 1.3 months.

Statistical analysis. Recurrence rates were calculated bythe Kaplan–Meier method, and the difference of the recurrence

rate was analyzed with the log–rank test. P < 0.05 was consideredstatistically signicant. Risk factors of lymph node metastasis aftersurgery were analyzed with Cox regression model. All statisticalanalysis was performed using IBM SPSS version 21.0 (IBMCorp., Armonk, NY, USA).

Results

Tumor metastatic recurrence and prognosis. Of theenrolled one hundred seventy four patients, 98 patients (56.32%)experienced the recurrence and metastatic disease. The mediandisease free interval was 25.5 ± 1.1 months (Fig. 1). The mode of rst recurrence of the tumor included lymphatic metastatic recur-rence in 54 cases, hematogenous metastasis in 21 cases, lymphaticmetastatic recurrence and blood born metastasis in 23 cases. Lym-phatic metastatic recurrence in pN0 Esophageal Squamous cellCarcinoma Patients after Ivor-Lewis Esophagectomy is shown inFigure 2. The 5-year survival probability in this group of patientsis shown in survival curves (Fig. 3).

STMN-1 protein expression analysis in tumor tissue specimen. Immunohistochemical analysis of 174ESCC specimens revealed that 100 patients (57.47%) showedSTMN-1 protein overexpression, as shown in Figure 4b,c.STMN-1 protein expression was low or undetected in normalesophageal tissue (Fig. 4a). In ESCC specimens, STMN-1 proteinexpression was higher than in normal esophageal tissues.

Relationship between STMN-1 expression and lymphatic metastatic recurrence. Based on the immu-nohistochemical analysis of STMN-1 protein expression, in 100patients with STMN-1 protein overexpression, 52 (52.00%) of our cases had lymphatic metastatic recurrence, while of 74 patients

Figure 1 Overall recurrence rate of esophageal squamous cellcarcinoma patients after surgery.

Stathmin expression in esophageal cancer J Akhtar et al .





with lower or normal STMN-1 protein expression, only 25(33.8%) cases had lymphatic metastasis. There was a statisticallysignicant difference in lymphatic metastatic recurrence in lowSTMN-1 expression and overexpression patients (Fig. 5).

Based on the Western blotting analysis of STMN-1 proteinsexpression, in the recurrence-free group, STMN-1 protein levelwas 0.0982 ± 0.0234, while in the lymphatic recurrence groupSTMN-1 protein level was 0.9799 ± 0.0532. Statistical resultsshowed that in patients with high levels of STMN-1 expression,

the lymphatic recurrence rate was higher than in patients with lowSTMN-1 expression.

Based on both types of protein assay, the patients with higherSTMN-1 protein expression were accompanied by higher lym-phatic metastatic recurrence.

Multivariate Cox regression analysis of lymphatic metastatic recurrence. We performed multivariate Cox

regression analysis to identify variables that closely related to thelymphatic metastatic recurrence in pN0 ESCC patients. Resultsshowed that tumor T stage and STMN-1 overexpression are inde-pendent factors of lymphatic metastatic recurrence in pN0 ESCC(Table 2).

Discussion

ESCC is a malignant tumor with strong invasion and high fre-quency of lymph node metastasis. There are still about 40% of them that are found to be lymph node micro-metastasis by IHCand molecular biological methods. 8 The long-term survival of patients with mid-thoracic ESCC remains poor because of the highincidence of lymph node metastases and early recurrence evenafter curative surgery. 9–11 The embryological structure of theesophagus is different from other digestive tracts, especially inpresence of lymph-vessels in muscularis mucosae. Lymph nodemetastasis of esophageal cancer can occur when the primary tumoris very small. The lymphatic drainage of the esophagus is complexwith a rich lymphatic network, and lymph node metastasis maypresent as regional metastasis, skipping metastasis, or distantmetastasis. 12–14 The middle thoracic ESCC has bidirectional metas-tasis trend, including upward spread to neck and upper mediasti-num, and downward to thoracic lower mediastinum abdomen. 15

All of the above likely contribute to the high rate of local andregional lymph node recurrence after resection.

a b

c d

Figure 2 Imaging diagnosis of lymphaticmetastatic recurrence in pN0 esophagealsquamous cell carcinoma patients after Ivor-Lewis esophagectomy. (a, b, and c) Com-puted tomography scan showing lymphaticmetastatic recurrence, and (d) PET-CTshowing diagnosis of lymphatic metastaticrecurrence after surgery.

Figure 3 Overall survival curve of esophageal squamous cellcarcinoma patients.






A complete surgical resection is considered to be rst-line treat-ment for individuals with localized ESCC 16–18 and remains thesuperior therapeutic modality for patient with locally advanceddisease. On the basis of oncology, McKeown (three-incision)esophagogastrectomy with three-eld lymphadenectomy isregarded as the best approach for mid-thoracic ESCC. However,this procedure has been criticized because it is very invasive andhas a high incidence of complications. 19–22 Whether three-eldlymph node dissection should be performed in all patients with

thoracic esophageal carcinoma remains controversial. 23,24 Thereare different surgical approaches for mid-thoracic esophagealcancer worldwide. There is no single widely accepted standardapproach. In our department, we usually perform the Ivor-Lewisprocedure to treat mid-thoracic ESCC. Compared with three-eldlymph node dissection, the biggest drawback of Ivor-Lewisesophagectomy is that cervical lymph node metastatic lesionswould be out of reach. Some studies showed that locoregional

lymph nodes recurrence was the main pattern of tumor recurrenceafter Ivor-Lewis esophagectomy with two-eld lymph node dis-section. Dresner and Grifn reported a 5.7% of cervical noderecurrence 25 after Ivor-Lewis esophagectomy, and we reportedabout 15% incidence in our previous study, 26 which was slightlyhigher than that after the three-eld lymph node dissection.

Despite the development of advanced surgical techniques andmultimodality treatment for ESCC patients, patient outcomesremain unsatisfactory. In spite of the complete resection of esopha-geal cancer, one third of patients will experience lymphatic meta-static recurrence within 2–3 years. 27–29 The probability of 5-yearsurvival is less than 50%, even after complete surgical resection.This means that about half of the patients will have tumor relapseafter the surgery. Some reports showed that locoregional relapse(lymphatic metastatic recurrence) was the main pattern of relapseof disease. 11 Our previous study also showed that locoregionallymph node recurrence was the main pattern of tumor recurrenceafter Ivor-Lewis esophagectomy with two-eld lymph node dis-section 26,30 Many of the patients with postoperative locoregionalrecurrence died within 1 year, so controlling locoregional recur-rence might be an important measure to improve prognosis of patients with esophageal carcinoma, There is consensus on theadjuvant radiotherapy effectiveness to prevent the lymphatic meta-static recurrence, although there are some debates as to whether itcan increase overall survival or not. It is of clinical importance topredict lymphatic metastatic recurrence early and to take adjuvant

a b

c d

Figure 4 Expression analysis of thestathmin (STMN-1) protein by immunohisto-chemistry in esophagus and esophageal squa-mous cell carcinoma (ESCC) specimens. (a)Normal esophageal tissue shows no STMN-1protein expression. Original magnication,×400. (b) Strong STMN-1 protein expressionin ESCC specimen, STMN-1 expression wasmainly localized within cytoplasm. Originalmagnication, ×400. (c) Moderate STMN-1expression in ESCC specimen. Original mag-nication, ×400. (d) Low STMN-1 expressionin ESCC specimen. Original magnication,×400.

Figure 5 Lymphatic metastatic recurrence curve for patients withstathmin (STMN-1) protein expression. , STMN-1 overexpression;

, Low STMN-1 expression.






treatment in time. There are few reports about molecular indicatorsto tentatively predict lymphatic metastatic recurrence. 2,30

Stathmin-1 (STMN-1), also known as p17, p18, p19, 19 K,metablastin, oncoprotein 18, LAP 18, and Op18, is a 19 kDacytosolic protein, functions as an important regulatory protein of microtubule dynamics, and has been well characterized. 3 It hasbeen reported that STMN-1 is overexpressed in many humanmalignancies, such as leukemia, lymphoma, neuroblastoma, andovarian, prostatic, breast, and lung cancers, 4 and the modulation of its expression correlates with invasion and metastasis. The proteinexpression of STMN-1 has been explored and found to correlate toclinicopathological factors and poor prognosis in several cancersin different tissues, such as brain, 31 oral mucosa, 32 breast, 28,33,34

urothelial, 35 as well as ovarian 36 and uterine cervix. 37 Our previousstudy showed that stathmin is overexpressed in gastric cancer 5

Recently, some reports showed that STMN-1 is also related tolymph node metastasis. 6 Our previous research suggestedSTMN-1 gene expression is a predictor of prognosis in stage IIAESCC. But there are no data about STMN-1 association with

lymphatic metastatic recurrence in ESCC.Currently, the NCCN guidelines do not recommend post-

operative adjuvant chemo or radiotherapy in pN0 after completeresection of ESCC. In our present study, we validated theoverexpression of STMN-1 gene and its association with lym-phatic metastatic recurrence. Our data show that the patients withSTMN-1 overexpression are at higher risk of lymphatic metastaticrecurrence of the disease. These high-risk patients should be fol-lowed by chemo or radiotherapy to prevent relapse of the malig-nant disease. Our previous studies have shown that adjuvantradiation treatment can signicantly reduce the incidence of esophageal cancer lymphatic metastatic recurrence after Ivor-Lewis surgery. 29,30 This research suggested that the overexpressionSTMN-1 is closely associated with lymphatic metastatic recur-rence in pN0 ESCC. Therefore, STMN-1 might become a refer-ence index for clinical assessment of lymphatic metastaticrecurrence. Although previous reports and our research showedthat the STMN-1 is associated with lymph node and lymphaticmetastatic recurrence, the underlying mechanism is unclear.Several researchers have shown that p53 and p27Kip1 are cellcycle regulatory proteins and differentially expressed in differentcancers. For the purpose of determining possible underlyingmechanisms of lymphatic metastatic recurrence in ESCC subtypeof patient with high stathmin expression, we are performing labo-ratory research on p53, p27Kip1, and PI3K pathway to understandthe possible relationships between these regulatory proteins and

their inuence on stathmin. We suspect that coordinated changesin STMN-1 and p27 expression in ESCC may be signicant for atleast two reasons. First, STMN-1 expression in ESCC could beinterpreted as direct evidence of cell cycle entry, and this eventlikely follows a release of p27-mediated restrictions on cell pro-liferation. Second, p27 has been shown to directly bind to andinhibit STMN-1 in the context of cell migration. Microtubuledynamics are important not only for mitosis but also for cellmotility. p27 appears to interfere with STMN-1’s depolymerizingability, thus impairing the cytoskeletal remodeling required for cellmovement. Loss of p27-mediated regulation may potentiate aber-rant cell proliferation, migration, and/or loss of polarity duringearly tumorigenesis. P53-mediated negative regulation of stathmin/Op18 also plays an important role in cell-cycle control.To disclose possible interconnection and mechanism, we will con-tinue research on a molecular basis.

In conclusion, surgery still remains the mainstay for mid-thoracic ESCC in China. Even patients with pN0 ESCC who arecompletely resected will experience lymphatic metastatic recur-

rence. Our research demonstrates that the patients with STMN-1overexpression in ESCC are at higher risk of lymphatic metastaticrecurrence. The overexpression of STMN-1 gene in tumor tissuescan be used to predict lymphatic metastatic recurrence in pN0

ESCC as a molecular reference indictor.We strongly suggest that prospective study in ESCC subset

of patient with STMN-1 gene overexpression should be done.Perhaps this subset of patient can benet from postoperativeadjuvant radiotherapy.

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Table 2 Multivariate Cox regression analysis for risk factor of lymphatic metastatic recurrence in esophageal squamous cell carcinoma patients aftersurgery

Risk factors B SE Wald d.f. Sig. Exp (B) 95.0% condenceinterval for exp (B)

Lower Upper

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