Prognostic significance of high YY1AP1 and PCNA expression in colon adenocarcinoma

https://doi.org/10.1016/j.bbrc.2017.10.060Get rights and content

Highlights

  • YY1AP1 expression might play an important role in the tumorgenesis of colon adenocarcinoma.

  • YY1AP1 expression is related with colon adenocarcinoma patient M-class/distant metastasis.

  • High YY1AP1 indicates poor overall survival of colon adenocarcinoma patients.

  • Cox proportional-hazards model analysis indicated YY1AP1 as an independent predictor for overall survival.

Abstract

To investigate the relationship between YY1AP1 and various clinicopathological features of colon adenocarcinoma (COAD), we conducted immunohistochemical (IHC) analyses of human tissue microarrays. We found that YY1AP1 protein expression was significantly higher in tumor tissue of the colon and liver, and was significantly lower in tumor tissue of the kidney. An analysis that employed the SurvExpress database indicated that increased expression of YY1AP1 mRNA was significantly associated with the overall survival of COAD patients. To clarify the validity of YY1AP1 or PCNA as determined by the IHC analysis was performed on 59 paired samples from COAD and adjacent normal tissue. Statistically significant differences of immunoreactivity for YY1AP1 or PCNA protein expression was observed between COAD tissue and adjacent normal tissue. High protein expression levels of YY1AP1 and PCNA were also found to be significantly correlated with M-class and distant metastasis. We also determined that YY1AP1 was correlated with PCNA expression in COAD samples, and Kaplan-Meier survival curves indicated that YY1AP1 protein expression was significantly associated with poor survival. Finally, a univariate analysis demonstrated that YY1AP1 protein expression was related to YY1AP1 score, and multivariate analysis revealed that the YY1AP1 protein expression level was an independent risk factor of overall COAD survival. Taken together, our findings indicate that YY1AP1 expression plays an important role in the tumorigenesis and progression of COAD and could serve as a clinical prognostic indicator for COAD.

Introduction

Colorectal cancer (CRC) is the one most common human cancers and the fourth leading cause of cancer deaths worldwide [1]. CRC is a primary malignancy of the intestine and is often associated with smoking, drinking alcohol, the consumption of red and/or processed meat [2], and inflammatory bowel disease (IBD), including either ulcerative colitis or Crohn's disease. As a result, CRC has the highest prevalence in developed countries [3], [4]. Establishing the prognosis of CRC patients requires that tumor tissue be surgically removed and histopathologically examined to assess the depth of tumor cell invasion and the status of lymph nodes [5]. However, the complexity of tumor biology and other patient-related factors make it difficult to predict the survival and prognosis of CRC patients. The formation of CRC involves multiple pathways and stepwise genetic changes, such as the loss or mutation of adenomatous polyposis coli (APC), abnormal DNA methylation, chromosome loss, and mutations in the p53 or K-Ras genes [6]. Unfortunately, during the early stages of CRC, tumors are generally asymptomatic, and the molecular nature of colorectal carcinogenesis is still not very clear. Therefore, identifying molecular markers that can (1) help facilitate the early diagnosis and classification of CRC and (2) improve prognostic predictions for CRC patients should greatly benefit medical treatments for this disease [7].

The gene for human YY1-associated protein 1 (YY1AP1) maps to chromosome 1q22. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1, an activator of the YY1 transcription factor [8], and may be related to cancer [10], [11] and other diseases [9]. Mutations in the YY1AP1 gene cause grange syndrome and a fibromuscular dysplasia-like vascular disease. YY1AP1 proteins localize to the nucleus and are responsible for transcriptional regulation, DNA replication, and DNA repair. In smooth muscle cells, loss of YY1AP1 leads to cell cycle arrest, decreased cell proliferation, increased levels of the cell cycle regulator p21/WAF/CDKN1A, and severe dysfunction in TGF-β-driven differentiation [9]. Overexpression of YY1AP1 has previously been observed in hepatocellular carcinoma patients. Specifically, a Gene Set Enrichment Analysis (GSEA) coupled with an assessment of genomic copy number alterations revealed that, in aggressive hepatocellular carcinoma, YY1AP1 is a critical oncoprotein which is specifically activated in the presence of high expression levels of EpCAM and AFP (EpCAM + AFP+). Increased YY1AP1 expression promotes cell proliferation and is required for the maintenance of stem cell features in hepatocellular carcinoma. Conversely, YY1AP1 silencing eradicates oncogene addiction by changing the chromatin landscape and inducing massive apoptosis and tumor suppression. In changing the chromatin landscape, YY1AP1 also cooperates with YY1 to activate transcription of stemness regulators. Therefore, YY1AP1 may act as a key driver gene of cancer stemness [11]; however, the role of YY1AP1 in the carcinogenesis of CRC is not clear.

The multistage process of tumorgenesis is initiated by the uncontrolled growth of cells associated with proliferative proteins, such as proliferating cell nuclear antigen (PCNA) [12]. In this study, we retrospectively investigated the expression of YY1AP1 and PCNA in the formation and progression of colon adenocarcinoma (COAD) by using IHC methods to measure the expression of YY1AP1 and PCNA in tumor tissues. We further compared adenocarcinoma tissue and normal tissue in terms of various clinicopathological features that are pertinent to CRC prognosis. Finally, we assessed the role of YY1AP1 in the formation and progression of COAD.

Section snippets

Human tissue specimens

A multiple organ normal tissue microarray (catalog number: BN00011) and a multiple cancer tissue (catalog number: MC801) microarray were purchased from US Biomax (Rockville, MD, USA). The normal tissue microarray included 6 cases of 8 types of tissue (i.e. breast, colon, esophagus, kidney, liver, lung, rectum, and stomach tissues); the cancer tissue microarray included 8 cases of 10 common types of tumor tissue (i.e. from tumors of the breast, cerebrum, colon, esophagus, kidney, liver, lung,

Expression profiles of YY1AP1 protein in multiple human tumors

Immunoreactivity of YY1AP1 was determined by staining multiple types of tumor tissues from human patients, including breast, colon, esophagus, kidney, liver, lung, and stomach tissues. In so doing, a statistically significant difference between normal tissues and tumor tissues was detected. The upregulation of YY1AP1 expression was found to be significantly greater in tumor tissue than in normal tissue for the colon (adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma;

Discussion

Previous studies have indicated that the YY1 protein may be involved in carcinogenesis [22]; however, the functional role of YY1 in cancer cells remains controversial. YY1 is implicated in the tumorigenesis and metastasis of osteosarcoma and prostate cancers [23], [24]. Patients with colorectal cancer and positive YY1 expression have shown a significant decrease in overall survival compared to colorectal cancer patients with negative YY1 expression [25]. Moreover, nuclear expression of YY1 has

Conflict of interest

The authors have no conflict of interest.

Acknowledgements

This study was supported by research funds (105-G6-1(3)) from Institute of Preventive Medicine, National Defense Medical Center, Taiwan, 2017.

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