Correlation of IDH1 and B7single bondH3 expression with prognosis of CRC patients

https://doi.org/10.1016/j.ejso.2018.05.005Get rights and content

Abstract

Background

B7single bondH3 is an immuno-stimulatory glycoprotein that is overexpressed in cancer. However, its functional contributions to cancer development and progression are not well understood. In several reports, it was demonstrated that B7single bondH3 reprograms lipid metabolism and regulates glucose metabolism. Isocitrate dehydrogenase 1 (IDH1), a metabolic enzyme in the TCA cycle, its reaction product is involved in lipid synthesis. Thus, we aimed to identify a novel marker to predict the prognosis of CRC patients and to investigate the relationship between IDH1 and B7single bondH3.

Methods

We analyzed IDH1 and B7single bondH3 expression levels in 225 CRC specimens by immunochemistry. Moreover, in vitro studies were performed to demonstrate the correlation between IDH1 and B7single bondH3.

Results

Among 225 tissues, the positive rates of IDH1 and B7single bondH3 were 37.8% (85/225) and 87.6% (197/225), respectively. In CRC samples, IDH1 significantly correlated with B7single bondH3 expression (P = 0.044). Moreover, multivariate analyses revealed that high expression of both B7single bondH3 and IDH1 and a high tumor grade were related to the prognosis of CRC patients. Kaplan-Meier survival analysis revealed that patients with co-expression of IDH1 and B7single bondH3 had a poor overall survival. In SW480single bondB7single bondH3-EGFP cells, which highly express B7single bondH3, IDH1 was up-regulated. Similarly, knockdown of B7single bondH3 expression in Caco-2-shB7-H3 contributed to reduced IDH1 levels.

Conclusions

Although IDH1 and B7single bondH3 cannot be used as independent prognostic factors, co-expression of IDH1 and B7single bondH3 significantly correlated with the prognosis of CRC patients and may serve as a combined predictive marker. Thus, the correlation between IDH1 and B7single bondH3 has been proven in vivo and in vitro.

Introduction

Colorectal cancer (CRC) is one of the most ordinary types of gastrointestinal tumors in the world, with a morbidity and mortality that were ranked third in 2016 [1]. It has been estimated that in China 376, 3 new cases of CRC and 191, 0 CRC-related deaths occurred [2]. Over the last few years, surgical approaches and medical treatment have been significantly improved, however the therapeutic effects in CRC patients are still not sufficient and far from acceptable. Immunotherapy has become the fourth most substantial treatment strategy regarding the recurrence and metastasis of solid tumors. Immune checkpoints PD1 and its ligand PD-L1 have been proven to reduce anti-tumor responses [3], and the corresponding inhibitors have successfully been used in the clinic to treat cancer patients.

B7single bondH3 is an immunoregulatory trans-membrane glycoprotein that is expressed by T cells [4]. As a co-stimulatory molecule, B7single bondH3 mediates the second signal on the regulation of T lymphocyte activation and tolerance [5]. The B7single bondH3 receptor has not yet been identified and its adaptive immune function remains controversial. Several published studies have shown that B7single bondH3 plays an inhibitory role during the cellular immune response. B7single bondH3 is highly expressed in a variety of solid tumors, including CRC [6], gastric cancer [7], breast cancer [8], and lung cancer [9]. Increased expression of B7single bondH3 is related to poor patient outcome [10], [11]. In previous studies, it has been demonstrated that B7single bondH3 promotes cancer cell metastasis and invasion through the Jak2/Stat3 signaling pathway [12], [13]. Recently, B7single bondH3 has been reported to regulate glucose metabolism in breast cancer cells [4] and lipid metabolism in lung cancer cells [14] in vitro. Therefore, it is of significant interest to investigate if B7single bondH3 is implicated in aberrant metabolic reprogramming of CRC.

The isocitrate dehydrogenase (IDH) enzyme plays a role in catalyzing the oxidative decarboxylation of isocitrate to produce α-ketoglutarate, in which NADP+ is used as a cofactor to maintain the cellular redox status and produce NADPH [15]. By bypassing the oxidative TCA cycle, reductive carboxylation and NAPDH facilitate the flux of carbons to synthesize AcCoA that is required for de novo lipogenesis. In two IDH encoding genes (IDH1 and IDH2), oncogenic mutations have been identified in acute myeloid leukemia [16], low-grade glioma, and secondary glioblastoma (GBM). The IDH1 R132H mutation confers a gain-of-function activity by simultaneously consuming NADPH and reducing α-KG to produce D-2-hydroxyglutarate (D2HG) [17]. Based on this, Calvert et al. [18] demonstrated that in primary GBM, a significant upregulation of wild-type IDH1 was observed to support tumor progression. Moreover, Koseki et al. [19] demonstrated that the imbalance between expression of IDH1 and IDH2 reduced the expression of HCDH4, thereby causing a decrease in DFS and OS in CRC patients. Currently a link between the expression of wild-type IDH1 and CRC patient survival is unprecedented.

Recently, research focusing on the effects of tumor-related immune molecules on metabolic reprogramming has received increased attention. In this study, we investigated the expression of IDH1 and B7single bondH3 in CRC and evaluated the correlation between these two genes using data collected from both clinical samples and stably transfected cell lines. Our results demonstrated that simultaneous expression of B7single bondH3 and IDH1 indicated CRC patients with poor prognosis, and the expression of B7single bondH3 and IDH1 was significantly correlated both in vivo and in vitro.

Section snippets

Patients and tissue specimens

This study was approved by the ethics committee of the Affiliated Hospital of Jiangnan University (Wuxi, China). All patients or guardians gave informed consent prior to the start of the study. The diagnosis and treatment records of 225 CRC patients were examined between June 2006 and November 2011 at the Department of Pathology, Affiliated Hospital of Jiangnan University (Wuxi, China). Clinicopathological features of patients are presented in Table 1. A total of 225 CRC patients who underwent

Patient characteristics

The clinicopathological parameters of 225 CRC patients are presented in Table 1. The study cohort comprised 127 males and 98 females. The age at initial diagnosis was classified as < 60 years (37.8%) or ≥60 years (62.2%) and the tumor locations were distributed in the colon (n = 88) and rectum (n = 137). Lymph node metastasis (N1single bondN3) was observed in 46.7% of cases. According to the pathological classification, 113 (50.2%) cases had stage Ⅰ–Ⅱ disease and 112 (49.8%) cases had stage Ⅲ–Ⅳ disease.

Expression of IDH1 and B7single bondH3 in CRC patients

In

Discussion

By increasing our understanding of the tumor microenvironment, previous studies have demonstrated that a tumor is not simply a stack of tumor cells, but an ecosystem consisting of tumor cells, infiltrating immune cells and interstitial cells, and other related molecules. Negative costimulatory molecules are important factors that affect tumorigenesis and development [3]. Furthermore, compelling evidence gained from experimental and epidemiological studies supported a critical role of gene-diet

Conflicts of interest statement

The authors declare no conflicts of interest.

Ethical approval

All procedures used in studies involving human participants were in accordance with the ethical standards of the Affiliated Hospital of Jiangnan University (Wuxi, China).

Informed consent

Informed consent was obtained from all participants enrolled in the study.

Acknowledgements

This study was supported by grants from the National Natural Science Foundation Youth Project of China (No. 81502042) and a grant from the Natural Science Foundation of Jiangsu Province (No. 20171150).

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