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Year : 2015  |  Volume : 11  |  Issue : 2  |  Page : 319-323

Expression of activating transcription factor 7 is correlated with prognosis of colorectal cancer

1 Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University; Department of Medical Oncology, Henan Province Cancer Hospital of Zhengzhou University, Zhengzhou 450 008, China
2 The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510 060, China
3 Department of Medical Oncology, Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan 523 808, China

Date of Web Publication7-Jul-2015

Correspondence Address:
Hong-Qiang Guo
Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University; Department of Medical Oncology, Henan Province Cancer Hospital of Zhengzhou University, Zhengzhou 450 008
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.148688

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 > Abstract 

Background: It is important to identify some tumor-related factors for early detection, treatment, and evaluation of prognosis in colorectal cancer (CRC). In our study, we inveatigated the clinical and prognostic role of activating transcription factor 7 (ATF7) in CRC.
Materials and Methods: Expression of ATF7 was detected with immunohistochemistry in 72 cases with complete follow-up data and post-operation tissue specimens. Correlation between ATF7 and other clinicopathological factors was calculated with Chi-square test and the impact of ATF7 on survival were analyzed with Log-rank test and Cox regression models.
Results: Among 72 cases, ATF7 expression was detected in 43 cases (59.7%) and 29 cases (40.3%) without ATF7 expression. The correlation between ATF7 expression and pathological stage was investigated (P = 0.041). The 5-year overall survival (OS) of with or without ATF7 expression was 79% versus 51% respectively (P < 0.001) and the 5-year progression free survival (PFS) was 74% versus 41% (P < 0.001). The media OS was 69 months versus 52 months (P = 0.002) and the media PFS was 65 months versus 42 months (P = 0.002). ATF7 expression and numbers of lymph nodes involvement were prognostic factors for OS according to univariated and multivariated analysis and for PFS it was ATF7 expression and lymph nodes involvement.
Conclusion: It is negatively related between ATF7 expression and pathological stage and positive correlation with OS and PFS in CRC. ATF7 expression is a favorable factor for survival of patients with CRC.

Keywords: Activating transcription factor 7, colorectal cancer prognosis, pathological stage

How to cite this article:
Guo HQ, Ye S, Huang GL, Liu L, Liu OF, Yang SJ. Expression of activating transcription factor 7 is correlated with prognosis of colorectal cancer. J Can Res Ther 2015;11:319-23

How to cite this URL:
Guo HQ, Ye S, Huang GL, Liu L, Liu OF, Yang SJ. Expression of activating transcription factor 7 is correlated with prognosis of colorectal cancer. J Can Res Ther [serial online] 2015 [cited 2020 Jul 16];11:319-23. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/319/148688

 > Introduction Top

Colorectal cancer (CRC) is one of the common causes of death. It is the third malignant tumor type for the death in the United States. [1] Now-a-days the incidence of CRC is increasing in China every year, especially in some developed regions. It is important to identify some tumor-related factors for early detection, treatment and evaluation of prognosis in CRC. Our previous study discovered that P63 activating transcription factor-1 (ATF1) and could be independent prognostic factors for CRC. [2],[3]

The ATF or cAMP-responsive element binding (CREB) family represents a large group of basic-region leucine zipper transcription factors. [4] Many members in the ATF/CREB family such as ATF1, ATF2, ATF3 and ATF6, are associated with oncogenesis, cell growth and apoptosis. [3],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] Human ATF7 was first isolated from Hela cell cDNA library and a novel member of ATF/CREB. [16] It has a number of sequence homology with ATF2, especially the C-terminal DNA-binding domain and the N-terminal activating domain. [17] The latter domain includes two conserved threonine residues. The conserved threonine residues of ATF7 are phosphorylated by different mitigen-activated protein kinases, especially JNK and p38 families, which lead to transcriptional activation. [18],[19],[20] Expression of ATF7 is found in many different tissues, and is related to intestinal differentiation. [21] The role of ATF7 in the occurrence and development of tumor has not been addressed. Our study was primarily to investigate the relationship between the expression of ATF7 and clinicopathological factors and analyze the prognostic value in CRC.

 > Materials and methods Top

Clinical materials

All clinicopathological data of 72 CRC patients were collected [Table 1]. Complete clinicopathological and follow-up data of these patients were gained. All tissue samples after operation were diagnosed as CRC by two experienced pathologists. Pathological stage was performed strictly according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer. Among them, the media age was 58 ranges from 30 to 85 years old with 39 males and 33 females. 5-Fu/CF based regimen was performed in 53 patients after operation and 13 cases without chemotherapy. Pathological stage of 72 cases included 8 cases at stage I, 40 cases stage II, 22 cases stage III and 2 cases stage IV. The median follow-up time was 84 months. Informed consent was taken from all subjects, and our study was approved by the Institutional Ethics Committee.
Table 1: Clinicopathological characteristics of 72 cases with CRC

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Tissue specimens were fixed in formalin solution and embedded with paraffins. 4 μm pathological sections were mounted onto the polylysine-coated slides, deparaffinized in xylene and hydrated in a gradient ethanol series. Finally, endogenous peroxidase was inactivated with 3% hydrogen peroxide. Then the sections were boiled in ethylene diamine tetraacetic acid (1 mmol/L; pH 8.0) for 15 min in a microwave oven for antigen retrieval and incubated with the mixture of 10% normal goat serum and phosphate-buffered saline (PBS) at room temperature for 1 h to block nonspecific protein binding. These sections were incubated with rabbit anti-ATF7 polyclonal antibody (Abcam Ltd., Hong Kong) at 37°C for an hour after removing the serum. After rinsing with PBS for three times, horseradish peroxidase-conjugated secondary antibody (ChemMate Envision Detection Kit, Dako, Denmark) was added on the sections and incubated for 30 min at room temperature according to the manufacturer's instruction. The specimens were stained with 3,3'-diaminobenzidine tetrahydrochloride and counterstained with hematoxylin after washing three times with PBS. The negative controls were performed under the same experimental condition without anti-ATF7 antibody. According to the staining cell numbers, negative expression (<5% positive cells) and positive expression (>5% positive cells) were differentiated.

Statistical analysis

The correlation between clinicopathological factors and ATF7 was analyzed with Chi-square test. Overall survival (OS) and progression free survival (PFS) were estimated with Kaplan-Meier method. Log-Rank test was used to evaluate the impact of ATF7 on the media PFS and OS. The prognostic effect of clinicopathological factors for PFS and OS was analyzed with univariate and multivariate analysis. OS was measured from the date of diagnosis to death, or last follow-up visit and PFS was measured from the date of diagnosis to relapse, death or last follow-up visit. The P < 0.05 with two-side test was considered as statistical significance.

 > Results Top

0Correlation of the activating transcription factor-7 expression with clinicopathological factors

Among 72 CRC patients, 43 cases (59.7%) were discovered the ATF7 expression and 29 cases without the ATF7 expression [Figure 1] and [Table 2]. ATF7 expression was significantly correlated with pathological stage (P = 0.041) and no significant association was found between ATF7 expression and gender, age, invasive depth, lymph nodes invasion, distant metastasis, peritumoral deposits, vascular tumoral emboli, primary tumor sites (colon or rectal) and adjuvant chemotherapy [Table 2].
Figure 1: Immunohistochemistry staining of activating transcription factor 7 (ATF7) (×200). (a) Negative expression of ATF7 in c olorectal cancer (CRC) epithelial cells; (b) positive expression of ATF7 in CRC epithelial cells

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Table 2: The correlation with clinicopathological characteristics and ATF7 expression

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The impact of activating transcription factor 7 on survival

We compared the PFS and OS according to the different ATF7 expression. The survival of patients in the group of ATF7 expression was significant longer than patients without ATF7 expression. The 5-year OS of with or without ATF7 expression was 79% versus 51% respectively (P < 0.001) and the 5-year PFS was 74% versus 41% (P < 0.001). The media OS was 69 months (95% confidence interval (CI): 63-75 months) versus 52 months (95% CI: 42-61 months) (P < 0.002) and the media PFS was 65 months (95% CI: 58-72 months) versus 42 months (95% CI: 31-53 months) (P = 0.002) [Figure 2].
Figure 2: Overall survival (OS) and progression free survival (PFS) according to the different activating transcription factor 7 (ATF7) expression. The 5-year OS of with or without ATF7 expression was 79% versus 51% respectively (P < 0.001) and the 5-year PFS was 74% versus 41% (P < 0.001). The media OS was 69 months (95% confidence interval (CI): 63-75 months) versus 52 months (95% CI: 42-61 months) (P = 0.002) and the media PFS was 65 months (95% CI: 58-72 months) versus 42 months (95% CI: 31-53 months) (P = 0.002)

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Prognostic effects of activating transcription factor 7 expression in colorectal cancer

According to univariate analysis, we found that the following factors including ATF7 expression, lymph nodes involvement (with or without lymph nodes involvement and numbers of lymph nodes involvement), pathological stage and peritumoral deposits had effect on PFS and OS. These factors, such as gender, age, primary tumor sites, invasive depth, vascular tumoral thrombosis and adjuvant chemotherapy, did not have correlation with PFS and OS. The results of multivariate analysis showed that ATF7 expression and number of lymph nodes involvement were independent factors for OS [Table 3]. ATF7 expression and lymph nodes involvement were independent factors for PFS. Therefore ATF7 expression was the independent factor for survival [Table 4].
Table 3: Univariate and multivariate analyses of clinicopathological factors for OS

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Table 4: Univariate and multivariate analyses of clinicopathological factors for PFS

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 > Discussion Top

Activating transcription factor 7 is a new member of ATF/CREB family. It has been discovered for two decade years, however its role in tumors has not been reported. Only Chen reported that down-regulation of ATF7 gene was detected with microarray in cervival cancer. [22] We collected 73 CRC tissues and found that 59.7% cases had ATF7 expression. We also found that negative correlation between pathological stage and ATF7 expression. It suggested that ATF7 expression might reduce tumor cell invasion and metastasis, and inhibit tumor cell grow. The results of survival analysis confirmed this view. Five-year survival, regardless of OS or PFS, was improved in the group of ATF expression. Therefore ATF7 was a tumor suppressor gene. However the mechanism of inhibiting cell proliferation, invasion and metastasis had not reported. It had been proved that the ATF7/c-Jun heterodimer is essential for ATF7 transactivation activity. [19] c-Jun was overexpressed in a range of cancers and stimulated the expression of lots of genes which could lead to cell proliferation and malignant transformation. [23],[24],[25] Higher expression of phosphorylated c-Jun had been discovered in CRC tissue compared with the adjacent normal tissue. [26] We hypothesized that in CRC the relation between ATF7 and c-Jun may be negative feedback. Peters reported that ATF7 physically interacted with the phosphatase of regenerating liver-1 (PRL-1) and concluded that PRL-1 was able to dephosphorylate ATF7 in vitro. [27] Overexpression of PRL-1 in epithelial cells resulted in tumor formation in nude mice. When PRL-1 was overexpression in 3T3 fibroblasts, growth characteristics including doubling time and morphology were altered. [28],[29] It had been reported that PRL-1 was widely expressed in human colorectal carcinoma cell lines (SW480 and SW620) and strongly expression in all lymph node metastases, but not primary adenocarcinomas. [30],[31] Therefore they thought PRL-1 may relate to the lymph node metastasis of colonic adenocarcinoma. [32] Maybe overexpression of PRL-1 led to ATF7 dephosphorylated and influenced the transcription of its downstream gene in CRC. Hence in that sense, ATF7 was an anti-oncogene.

We further analyzed 12 clinicopathological factors to ascertain the prognostic factors for PFS and OS in CRC. ATF7 expression and numbers of involved lymph nodes were independent factors for OS. ATF7 expression and lymph nodes involved or not were independent factors for PFS. Therefore ATF7 expression was good prognostic indicator for CRC. Pathological stage was associated with OS and PFS through univariate analysis. However, because cases in our study were centralized in stage II, multivariate analysis failed to prove pathological stage as an independent prognostic parameter.

 > Conclusions Top

Activating transcription factor 7 expression was negatively associated with pathological stage and positively correlated with OS and PFS. ATF7 could be an independent prognostic indicator for CRC. Our study suggested that ATF7 might be an anti-oncogene in CRC. Further study would explore the mechanism as an tumor suppressor gene in CRC.

 > References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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