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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 4  |  Page : 1291-1297

Increased expression of high-mobility group A2: A novel independent indicator of poor prognosis in patients with esophageal squamous cell carcinoma


1 Department of Gastroenterology, Tianjin Hospital of ITCWM, Nankai Hospital, Nankai, Tianjin 300100, China
2 Department of Urology, Second Hospital of Tianjin Medical University; Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300211, China
3 Department of Surgery, Tianjin Fourth Hospital, Tianjin 300222, China

Date of Web Publication7-Feb-2017

Correspondence Address:
Lihong Cui
Department of Gastroenterology, Tianjin Hospital of ITCWM, Nankai Hospital, Changjiang Road, Nankai, Tianjin 300100
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.180616

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 > Abstract 

Purpose: Although high-mobility group A2 (HMGA2) protein has been reported to participate in cancer progression and metastasis, its clinical relationship with tumor invasion, lymph node metastasis, and prognosis in esophageal squamous cell carcinoma (ESCC) remains unclear. The purpose of this study is to analyze the clinical and prognostic significance of HMGA2 in ESCC patients after curative resection.
Materials and Methods: The expression of HMGA2 protein was evaluated by using immunohistochemistry in a tissue microarray (TMA) containing ESCC lesions and adjacent normal esophageal epithelial tissues from 96 patients who had undergone curative resection. TMA was constructed by Shanghai Biochip Co. Ltd., Shanghai, China. The relationship between HMGA2 expression and clinicopathological parameters and prognosis was further analyzed.
Results: HMGA2 expression was significantly higher in ESCC tissues compared with that of the adjacent noncancerous tissues (P < 0.001). High expression of HMGA2 was significantly related to tumor size, lymph node metastasis, and advanced tumor-node-metastasis stage (P < 0.05). Patients with low expression of HMGA2 had a better prognosis than those with high expression (χ2 = 5.069, P = 0.024). Univariate analysis showed that age (P = 0.041), depth of tumor invasion (P = 0.031), lymph node status (P = 0.001), and HMGA2 expression (P = 0.024) were correlated with prognosis. Multivariate analysis showed that HMGA2 expression (hazard ratio [HR]: 0.539; 95% confidence interval [95% CI]: 0.302–0.963, P = 0.037) and lymph node metastasis (HR: 0.504; 95% CI: 0.310–0.820, P = 0.006) were independent prognostic factors for overall survival.
Conclusions: High HMGA2 expression was related to lymph node metastasis and poor prognosis in ESCC. Our results indicated that HMGA2 could act as a potential biomarker for prognosis evaluation of ESCC patients.

Keywords: Esophageal squamous cell carcinoma, high-mobility group A2 protein, lymph node metastasis, prognosis


How to cite this article:
Wei R, Shang Z, Leng J, Cui L. Increased expression of high-mobility group A2: A novel independent indicator of poor prognosis in patients with esophageal squamous cell carcinoma. J Can Res Ther 2016;12:1291-7

How to cite this URL:
Wei R, Shang Z, Leng J, Cui L. Increased expression of high-mobility group A2: A novel independent indicator of poor prognosis in patients with esophageal squamous cell carcinoma. J Can Res Ther [serial online] 2016 [cited 2020 Oct 24];12:1291-7. Available from: https://www.cancerjournal.net/text.asp?2016/12/4/1291/180616


 > Introduction Top


Esophageal cancer is the eighth most common type of cancer and the sixth leading cause of cancer-related mortality worldwide.[1] Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer in the world.[2] Although recent advances in multidisciplinary treatment have been achieved, the prognosis of patients with ESCC remains poor. One important factor that contributes to the poor prognosis is the propensity for metastasis even at a superficial level.[3] Given the high incidence and mortality rates of ESCC, there is a substantial need for clarifying the molecular mechanism and finding specific targets for invasion and metastasis to immediately detect and disturb the cancer progression and metastasis.

High-mobility group A2 (HMGA2) protein, an architectural transcription factor, could alter chromatin structure and regulate gene expression by binding to the AT-rich region of DNA.[4] Recently, emerging studies reported that HMGA2 was highly expressed in many human malignancies and participated in different cellular activities, including cell cycle regulation, differentiation senescence.[5],[6] Moreover, overexpression of HMGA2 has been reported to be correlated with tumor invasion, lymph node metastasis, and distant metastasis in pancreatic cancer,[7] colorectal cancer,[8] and so on, thereby indicating that HMGA2 is potentially involved in carcinogenesis. In many malignant neoplasms, including colorectal cancer,[8] oral squamous cell carcinoma,[9] and bladder cancer,[10] patients with HMGA2 overexpression had a poor prognosis. Taken together, all the mentioned evidence indicated that HMGA2 may participate in the important progress of neoplasm transformation and progression. In ESCC, most of the recent studies focused on the important role of HMGA2 in the molecular mechanism of tumor invasion and metastasis.[11] However, data on the clinical and prognostic significance of HMGA2 in patients with ESCC are limited.

Therefore, the purpose of this study is to investigate the expression level of HMGA2 between tumor and normal tissues, to determine whether HMGA2 has any potential role in the development and progression of ESCC, and to identify whether HMGA2 is a prognostic factor in ESCC after curative surgical treatment.


 > Materials and Methods Top


Patients and tissue specimens

Between January 2007 and December 2009, a total of 96 patients who underwent a complete surgical resection for histologically proven ESCC at hospitals that cooperated with the National Engineering Center for Biochip in Shanghai, China were enrolled into the present study. The eligibility criteria for the current study were as follows: (a) histologically confirmed primary thoracic ESCC, (b) no distant metastases, including supraclavicular or celiac lymph node metastases, (c) complete surgical resection (R0), and (d) complete basic clinical and follow-up data. None of these patients had a previous history of cancer, and none had received any preoperative therapies such as chemotherapy or radiotherapy. Patients with a noncurative resection or who died within 30 days of surgery were excluded from the study.

Tumor location was classified as upper, middle, and lower third of the esophagus. Histological grading was defined as well differentiated, moderately differentiated, or poorly differentiated/undifferentiated, according to the World Health Organization classification of esophageal tumors.[12] Tumor stage was determined according to the 7th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for esophageal carcinoma.[13] With regard to depth of tumor invasion, tumor that invades lamina propria, muscularis mucosae, or submucosa was defined as T1; tumor that invades muscularis propria was defined as T2; tumor that invades adventitia was defined as T3; and tumor that invades adjacent structures was defined as T4.

This study was approved by the Ethical Committees of the host institution and the National Engineering Center for Biochip in Shanghai, China. Written informed consent was obtained from each patient before participation in our study. Paraffin-embedded tumor specimens and their paired adjacent nontumor specimens (≤1.5 cm away from the tumor) were carefully collected before the patients were treated with any anticancer therapy.

Clinical follow-up information was obtained by telephone or from outpatient records. All patients were followed up until June 2015 with a median observation time of 30 months ranging from 3 to 96 months. Finally, 73 (76.0%) patients died during follow-up.

Tumor tissue microarray

A tissue microarray (TMA) contains ESCC lesions and adjacent normal esophagus epithelial tissues of 96 cases were constructed as previously described.[14] Briefly, fresh sections were cut from the donor block and stained with hematoxylin and eosin. The slides were reviewed by a pathologist to identify the optimal intratumoral and peritumoral tissue to use for TMA construction. A tissue array (Beecher Instruments, Sun Prairie, WI, USA) was used to create holes in a recipient paraffin block and to acquire tissue cores from the donor block by using a thin-walled needle with an inner diameter of 600 µm, held in an X-Y precision guide. Subsequently, sections (4 µm thick) were cut from the array blocks and prepared for immunohistochemistry (IHC) analysis.

Immunohistochemistry

Immunohistochemical staining was performed using the previously described streptavidin–biotin method to detect HMGA2 protein expression level. TMAs were baked followed by deparaffinization with xylenes and rehydrated through graded alcohol. Antigen retrieval was performed by autoclaving the slides using microwave treatment for 10 min in 0.01 M sodium citrate buffer (pH 6.0). Endogenous peroxidase activity was blocked by incubating the sections in methanol with 3% hydrogen peroxide at room temperature. Sections were incubated with 1:200 dilution of rabbit polyclonal anti-HMGA2 (Abcam, ab52039, UK) overnight at 4°C in a humidity chamber. Sections incubated with PBS replacing the primary antibody were used as negative controls. After being washed, the sections were treated with MaxVision HRP-Polymer anti-rabbit HIC Kit (Maixin Bio, Fujian, China) at 37°C for 30 min. Diaminobenzidine was used as chromogen; the TMA was subsequently counterstained with hematoxylin, dehydrated, and mounted.

The sections were evaluated independently using light microscopy by two independent pathologists who were blinded to the clinicopathological information. Tumor cells with nuclear staining were considered positive. The expression of HMGA2 was scored by multiplying the staining intensity (0 = absent staining, 1 = faint staining, 2 = moderate staining, and 3 = strong staining) and the percentage of positively stained cells in the entire carcinoma-involved area of each tumor (0 = nonstaining, 1 = 1–10%, 2 = 11–50%, 3 = 51–80%, and 4 = >80% positive cells). To divide all 96 ESCC patients into high HMGA2 expression and low HMGA2 expression groups, a cutoff value for HMGA2 expression levels was determined based on a measure of heterogeneity using the log-rank test statistic with respect to overall survival (OS) as previously published.[15],[16] Finally, patients were subsequently categorized into two groups: a staining index score of ≥4 was considered as high HMGA2 expression, whereas a staining index score of ≤3 was considered as low HMGA2 expression.

Statistical analysis

All statistical analyses were performed by using SPSS version 19.0 software package (SPSS, Inc., Chicago, IL, USA). Quantitative variables were compared using the Student's t-test and expressed as median ± standard deviation. The association between HMGA2 protein expression and clinicopathological variables were analyzed by Pearson χ2 test or Fisher's exact test. OS was defined as the time from the date of surgery to the date of last contact or death from any cause. Survival analysis was calculated by using the Kaplan–Meier method and the difference of survival was evaluated by log-rank test. Univariate and multivariate analyses were performed using Cox's proportional hazards model to identify the significant prognostic factors related to OS. Hazard ratio (HR) and corresponding 95% confidence interval (95% CI) were calculated. Two-sided P < 0.05 was considered as statistically significant.


 > Results Top


Clinicopathological characteristics of esophageal cancer patients

The main clinicopathological characteristics of the research subjects are summarized in [Table 1]. The subjects consisted of 77 males and 19 females. The median age was 65 years, ranging from 39 to 76 years. The tumors were mainly located in the middle (83.3%) esophagus. The tumor size of 58 patients was ≤4 cm and that of 38 patients was more than 4 cm. According to the histological grading in these cancer tissue blocks, 11 (11.5%) tissues were poorly differentiated, 80 (83.3%) were moderately differentiated, and 5 (5.2%) were well-differentiated.
Table 1: Patient demographics and clinicopathological characteristics

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Based on the criteria of the AJCC TNM staging system, 17 patients with T1/T2 and 79 patients with T3/T4. Furthermore, 44 patients had positive lymph node metastasis, whereas 52 had negative. In addition, four cases were classified as stage I tumors, 24 cases were classified as stage II, and 68 cases were classified as stage III.

For patients who suffered from advanced disease, postoperative adjuvant therapy was administered after surgery. Several patients satisfied the criteria but did not receive adjuvant therapy. Finally, 56 (58.3%) patients received chemotherapy, radiotherapy, or both in the postoperative period.

Expression of high-mobility group A2 protein in resected esophageal squamous cell carcinoma and adjacent normal esophagus epithelial tissues

The expression and localization of HMGA2 protein were tested by IHC in 96 resected ESCC tissues and corresponding normal esophagus epithelial tissues. As shown in [Figure 1], positive expression of HMGA2 protein was mainly located in the cell nuclei, and undetectable or low expression of HMGA2 protein was found in the cancer cell membranes and cytoplasm. The intensity of HMGA2 protein expression in the 96 tumor tissue samples was 69.8% (67/96), which was significantly stronger than that in the matched adjacent normal tissue samples (36.5%, 35/96) (P < 0.001).
Figure 1: Immunohistochemical staining of high-mobility group A2 protein in esophageal squamous cell carcinoma and matched normal esophagus epithelial tissues (IHC, ×200). (a) Negative staining of high-mobility group A2 in a noncancerous tissue sample, (b) strong intensity staining of high-mobility group A2 in esophageal squamous cell carcinoma tissues

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Correlation of high-mobility group A2 expression and clinicopathological characteristics of patients with esophageal squamous cell carcinoma

The correlation between HMGA2 expression and clinicopathological characteristics in the 96 ESCC cancer specimens was investigated and described in [Table 2]. The results showed that the HMGA2 expression was significantly associated with tumor size (P = 0.013), lymph node metastasis (P = 0.018), and advanced TNM stage (P = 0.042). However, no statistical differences were observed between the expression of HMGA2 and gender, age, smoking history, tumor location, histological grade, and depth of tumor invasion (P > 0.05). Detailed data are shown in [Table 2].
Table 2: Association of high-mobility group A2 expression with different clinicopathological features of esophageal squamous cell carcinoma patients

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Prognostic value of high-mobility group A2 protein expression in patients with resected esophageal squamous cell carcinoma

The 1-, 3-, and 5-year survival rates for all patients with resected ESCC were 78.1%, 51.0%, and 30.2%, respectively. The median survival time was 24 months (95% CI: 15.883–32.117).

To further analyze the prognostic value of HMGA2 expression in patients with resected ESCC, survival analysis using Kaplan–Meier survival curve and log-rank test demonstrated that patients with HMGA2 lower expression in cancer tissue had significantly better OS than patients with higher HMGA2 expression (48.3% vs. 22.4%, χ2 = 5.069, P = 0.024) [Figure 2]. In addition, as shown in [Figure 3], the 5-year survival rate and median survival time of ESCC patients with negative lymph node metastasis were better than those of patients with positive lymph node metastasis (44.2% vs. 13.6%, χ2 = 13.166, P = 0.001).
Figure 2: Kaplan–Meier survival curves of patients with esophageal cancer. Patients with higher high-mobility group A2 expression have a significantly worse overall 5-year survival than patients with lower expression (P = 0.024)

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Figure 3: Kaplan–Meier survival curves of patients with esophageal cancer. Patients with negative lymph node metastasis had a significantly better overall 5-year survival than patients with positive lymph node metastasis

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As shown in [Table 3], Cox regression univariate analysis indicated that age (P = 0.041), depth of tumor invasion (P = 0.031), lymph node metastasis (P = 0.001), and HMGA2 expression (P = 0.024) were negative prognostic factors [Table 3].
Table 3: Univariate Cox regression analysis of overall survival in patients with resected esophageal squamous cell carcinoma

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Multivariate Cox proportional hazard analysis revealed that only lymph node metastasis (HR: 0.504; 95% CI: 0.310–0.820, P = 0.006) and HMGA2 expression (HR: 0.539; 95% CI: 0.302–0.963, P = 0.037) were independent prognostic factors for OS [Table 4].
Table 4: Multivariate Cox regression analysis of overall survival in patients with resected esophageal squamous cell carcinoma

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 > Discussion Top


The malignant characteristic of propensity for invasion and metastasis is one of the main factors that contribute to the poor outcome of patients with ESCC.[3] Therefore, elucidating the molecular mechanism of ESCC in invasion and metastasis as well as further finding the corresponding molecular targets will ultimately improve the prognosis for these patients. Emerging data revealed that HMGA2, a nonhistone chromosomal architectural protein, is correlated with tumor grade, progression, and metastasis in many malignant neoplasms, including ESCC,[11] pancreatic carcinoma,[6],[7] and colorectal carcinoma.[10] To date, studies on ESCC have elaborated the role of HMGA2 in tumor invasion and metastasis from the molecular mechanism point of view.[11] However, limited evidence reported the correlation between HMGA2 and clinicopathological variables as well as the prognosis from the clinical point of view. In the present study, we performed the first systematic expression analysis of HMGA2 on a cohort of ESCC specimens and subsequently identified potential roles for HMGA2 in the development and progression of ESCC.

In 1998, Kononen et al.[17] introduced TMAs as a powerful technology to rapidly visualize molecular targets such as genes and gene products in thousands of tissue specimens simultaneously. In the current study, a TMA with 96 specimens from Chinese esophageal cancer and 96 specimens from adjacent nontumorous tissues was constructed to analyze the clinical relationship between the expression of HMGA2 as well as clinicopathological factors and prognosis in patients with ESCC. Our findings revealed that HMGA2 was mainly expressed in the nuclei of cancer cells, and the positive rate of HMGA2 protein expression in ESCC tissues was remarkably higher than that in adjacent noncancer tissues (P < 0.001). This finding has potential clinical importance for early diagnosis. Furthermore, higher expression of HMGA2 protein was significantly associated with tumor size (P = 0.013), lymph nodes metastasis (P = 0.018), and advanced TNM stage (P = 0.042), which indicates that HMGA2 is associated with aggressiveness and plays an important role in the metastasis process in ESCC. In our study, the percentage of patients with T3/T4 showing HMGA2 overexpression was higher than that in patients with T1/T2, but no significant correlation was found between HMGA2 expression and depth of tumor invasion. This result may be attributed to the small sample size; thus, further verification is needed.

Recent studies on gastric cancer,[18],[19] colorectal cancer,[8] pancreatic cancer,[7] and oral squamous cell carcinoma [9] also showed the similar results that high HMGA2 expression was related to tumor invasion and lymph node metastasis. The oncogene HMGA2 is widely known to be capable of altering the chromatin structure by binding to the minor groove of DNA in the AT-rich region.[4] However, the underlying molecular mechanism of HMGA2 that elicits ESCC invasion and metastasis is not well understood.

The epithelial–mesenchymal transition (EMT) has been reported to play a critical role in tumor invasion and metastasis.[20] Recently, more and more studies on various malignancies have reported that HMGA2 participated in tumor progression, invasion, and metastasis by inducing EMT.[21],[22],[23],[24] Moreover, overexpression of HMGA2 resulted in the molecular changes consistent with EMT, including the downregulation of E-cadherin expression.[23],[25],[26] Thuault et al.[27] deciphered the EMT signal pathway mediated by HMGA2, and described that transforming growth factor-beta induced the HMGA2 expression through Smad pathway, and then HMGA2 and Smad cooperatively regulated the E-cadherin expression by binding to Snail and elicited the EMT. At the same time, extracellular matrix degradation was also one key progress of invasion and metastasis;[28] in ovarian carcinoma, HMGA2 may downregulates the expression of matrix metalloproteinase 2 and 9, as well as increase the invasion capacity.[21]

Previous data showed that patients with a high level of HMGA2 expression were associated with poor prognosis, including colorectal carcinoma,[8] bladder cancer,[10] nasopharyngeal carcinoma,[29] and melanoma.[30] However, the prognostic role of HMGA2 expression in patients with ESCC has not been reported. Thus, in the present study, we initially analyzed the relation between the protein levels of HMGA2 and the outcome of ESCC patients; we further analyzed the clinicopathological parameters associated with prognosis in patients with ESCC by univariate and multivariate analyses. In agreement with the preceding studies, our results demonstrated that ESCC patients with a high level of HMGA2 protein expression had an unfavorable prognosis compared with patients with a low level of HMGA2 expression, providing evidence that the elevated expression of HMGA2 in ESCC might facilitate an increased malignant and worse prognostic phenotype of this tumor. Notably, when the expression of HMGA2 proteins as well as other parameters was examined in multivariate Cox analysis, the HMGA2 expression was identified as an independent indicator of patient survival in this study. In addition, our present study identified that lymph node involvement may be an independent prognostic factor for esophageal cancer, which was consistent with the results of previous studies.[13]

Based on the previous evidence in various tumor types that HMGA2 overexpression was associated with poor prognosis and lymph node metastasis,[7],[31],[32] we inferred that HMGA2 expression affected the survival of patients with ESCC by inducing tumor invasion and lymph node metastasis. Our results might have certain clinical implications. ESCC patients with HMGA2 overexpression might benefit from closer follow-up and aggressive treatment. In the future, overexpression of HMGA2 could be used as a prognostic marker for predicting outcome and a therapeutic target for disturbing lymph node metastasis and distant metastasis in patients with ESCC.

To the best of our knowledge, this is the first study to analyze the role of HMGA2 expression from a clinical point of view. Our findings indicated that high expression of HMGA2 was related to lymph node metastasis and poor prognosis in resected ESCC. However, the current study was based on retrospective analysis and semiquantitative research. Further research is needed to elucidate the role and significance of HMGA2 in the ESCC setting, and HMGA2 may be regarded as a valuable prognostic biomarker and potential therapeutic target in ESCC patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
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