Hindawi
Disease Markers
Volume 2019, Article ID 2312439, 12 pages
https://doi.org/10.1155/2019/2312439
Research Article
Prognostic Significance of CIP2A in Esophagogastric Junction
Adenocarcinoma: A Study of 65 Patients and a Meta-Analysis
Yanhong Li ,1,2 Mei Wang,3 Xueping Zhu ,4 Xu Cao ,5 Yi Wu ,1,6 and Fang Fang
1
1
Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, 215025 Jiangsu, China
Department of Nephrology, Children’s Hospital of Soochow University, Suzhou, 215025 Jiangsu, China
3
Department of Pharmacy, Children’s Hospital of Soochow University, Suzhou, 215025 Jiangsu, China
4
Department of Neonatology, Children’s Hospital of Soochow University, Suzhou 215025, China
5
Department of Surgery, Children’s Hospital of Soochow University, Suzhou, 215025 Jiangsu, China
6
Department of Pathology, Children’s Hospital of Soochow University, Suzhou, 215025 Jiangsu, China
2
Correspondence should be addressed to Yi Wu; and Fang Fang; baseff
[email protected]
Received 12 March 2019; Revised 28 May 2019; Accepted 16 July 2019; Published 22 August 2019
Academic Editor: Benoit Dugue
Copyright © 2019 Yanhong Li et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. The expression of the cancerous inhibitor protein phosphatase 2A (CIP2A) appears to be predictive of the prognosis of
various solid tumors. However, the association between this protein and the risk of esophagogastric junction adenocarcinoma
(EGJA) remains unclear. We investigated CIP2A expression and its clinical significance in EGJA and conducted a meta-analysis
to explore the relationship between CIP2A and the prognosis of patients with solid tumors. Methods. Immunohistochemistry
(IHC) was performed to detect the expression of CIP2A in EGJA. Kaplan-Meier estimation, Cox analysis, and ROC curves
were performed to analyze the survival of patients and the prognostic factors. In the meta-analysis, we searched relevant
publications in several widely used databases and used 15 studies (2348 patients). Results. IHC demonstrated that CIP2A
was elevated in EGJA and correlated with poor survival as an independent indicator. It could forecast the survival more
precisely when combined with the grade, which is another independent prognosis marker of EGJA. Meta-analysis
demonstrated that the associations between the expression of CIP2A and the prognosis were detected for overall survival
(HR = 1 98, 95%CI = 1 69‐2 32), disease-specific survival (HR = 1 72, 95%CI = 1 50‐1 97), and time to tumor progression
(pooled HR = 1 95, 95%CI = 1 56‐2 43). Conclusion. High expression of CIP2A was a poor indicator of the prognosis of EGJA,
and CIP2A may be a new biomarker for the diagnosis and treatment of EGJA. The meta-analysis suggested that CIP2A
expression can be a predictive marker of overall survival, disease-specific survival, and time to tumor progression in patients
with solid tumors.
1. Introduction
Esophageal squamous cell carcinoma (ESCC) and gastric carcinoma (GC) are common tumors and the leading causes of
cancer-related deaths worldwide [1]. Esophagogastric junction adenocarcinoma (EGJA) is considered a unique clinical
malignancy with different etiology, clinicopathological features, and biological behaviors than ESCC and GC. EGJA is
defined as a cancer across the esophagogastric junction line,
including distal esophageal adenocarcinoma and proximal
gastric cancer [2, 3]. Chronic gastroesophageal reflux disease
is a strong risk factor for EGJA and leads to intestinal meta-
plasia (Barrett’s esophagus) [4]. Interestingly, Helicobacter
pylori infection, a risk factor for gastric cancer, is considered
a protective factor for EGJA for its prevention of reflux
esophagitis and Barrett’s esophagus [5]. The treatment strategy for EGJA is complex because of the anatomical location
of the esophagogastric junction. The incidence of EGJA has
shown an increasing trend over the past few decades with a
poor prognosis [6, 7]. There is therefore an urgent need to
reveal novel molecular markers to provide new strategies
for EGJA treatment and improve patient outcomes.
Cancerous inhibitor protein phosphatase 2A (CIP2A)
is an oncoprotein [8]. It is encoded by KIAA1524 and
2
functions through an “oncogenic nexus” [9]. The “oncogenic
nexus” consists of various functions of CIP2A, including the
inhibitory effects on protein phosphatase 2A, interactions
with MYC protein, and effects on the mechanistic target
rapamycin kinase (MTOR) [10]. Although CIP2A has been
suggested to influence the prognosis of various cancer types
[11–13], the role of CIP2A in EGJA remains unknown.
This study investigated the clinical significance of CIP2A
in EGJA by detecting the expression of CIP2A in EGJA and
paracancer tissues, providing a basis for clinical diagnosis,
prognosis, and treatment guidance. Furthermore, we investigated the relationships between CIP2A and solid cancer
prognosis systematically and statistically based on previous
studies that focused on this relationship. A total of 15 studies
with relatively large sample sizes (2348 patients total) were
selected [14–28], and a meta-analysis was conducted to
provide a more reliable assessment of the relationship
between CIP2A and solid cancer prognosis.
2. Materials and Methods
2.1. Specimen Collection. The clinical tissue microarray of
esophagogastric junction adenocarcinoma (HGEj-Ade130Sur-01) was purchased from Outdo Biotech Co. (Shanghai,
China). Hematoxylin- and eosin-stained (HE) sections were
used to determine the pathological and cytological diagnosis
by pathologists based on the WHO Classification of Tumors.
This study was approved by the Medical Ethical Committee
of Children’s Hospital of Soochow University.
2.2. Immunohistochemistry. According to the manufacturer’s instructions, a catalyzed signal amplification system
kit (Boster, Wuhan, China) microarray was deparaffinized,
rehydrated, and the antigens retrieved. Sections were then
incubated with the primary antibody (Anti-CIP2A, Santa
Cruz Biotechnology, Santa Cruz, CA, USA) at a dilution
of 1 : 100. The secondary antibody, developed using DAB,
was counterstained with hematoxylin and observed under
a microscope.
To determine the immunoreactivity scores (IRSs), the
microarray was scored and evaluated by 3 investigators. Positive cells exhibited yellow or yellow-brown granules in the
cytoplasm and/or nucleus. The staining intensity was scored
as follows: colorless (no staining) was 0 points, light yellow
(weak staining) was 1 point, yellow-brown (moderate staining) was 2 points, and brown (strong staining) was 3 points.
The percentage of positive cells was scored as follows: ≤25%
positive cells were scored as 1 point, between 26% and 50%
positive cells were scored as 2 points, between 51% and
75% positive cells were scored as 3 points, and >75% posit (...truncated)
