Decreased circadian component Bmal1 predicts tumor progression and poor prognosis in human pancreatic ductal adenocarcinoma

https://doi.org/10.1016/j.bbrc.2016.02.087Get rights and content

Highlights

  • The expression of Bmal1 is decreased in human pancreatic ductal adenocarcinoma (PDA).

  • Decreased Bmal1 expression correlates with advanced TNM stage and poor histological differentiation of PDA.

  • Low Bmal1 expression is an independent prognostic factor for poor survival outcome for patients with PDA.

Abstract

The circadian clock has been demonstrated playing important roles in human tumorigenic process; however, the detailed clinical implications of circadian disruption on tumors have not been well understood. In this study, we investigated the expression pattern of Bmal1, the core component of the circadian system, in human pancreatic ductal adenocarcinoma (PDA). Our immunohistochemistry analysis showed that the protein level of Bmal1 was significantly decreased in tumor tissues from 87 patients with PDA compared with adjacent non-cancerous tissues. Low Bmal1 expression was associated with the TNM/clinical stage, histological differentiation, and vascular invasion of PDA; but no significant relevance to patient age, gender, the tumor location, or the size. Furthermore, Kaplan–Meier survival analysis revealed that PDA patients with low Bmal1 expression had shorter overall survival (OS) times as well as disease-free times (DFS) compared to the patients with high Bmal1 expression. Lastly, univariate and multivariate analyses identified low Bmal1 expression as an independent prognostic factor for poor survival outcome for patients with PDA. Collectively, our present study demonstrated that the decreased expression of Bmal1 is correlated with the tumor progression and poor prognosis in human PDA, which implicated its potential to be used as a biomarker for diagnosis and prognosis of PDA.

Introduction

As one of the leading cause of cancer related death, pancreatic ductal adenocarcinoma (PDA) remains a dismal diagnosis, low survival rate, and high mortality for patients [1], [2]. Most PDA patients undergo chemotherapy or surgical techniques for treating are already at an advanced stage [3]. Therefore, new prognostic and predictive markers for a reliable and early detection of PDA is an urgent need currently, which, calls for a better understanding of the underlying mechanisms involved in the formation, development, and progression of PDA.

In mammals, it is established that an endogenous circadian clock that oscillates around 24 h influences nearly all the aspects of biological activities and behaviors [4], [5], [6]. The circadian clock system is operated by a central clock that located in the suprachiasmatic nuclei (SCN) and peripheral tissue oscillators, and is molecularly based on the feedback loops of a series of circadian genes such as Bmal1, Clock, Per1, Per2, Cry1, Cry2, TIM, andCK1ε [7]. These genes together with their specific downstream targets which are the so called clock-controlled genes (CCGs) including cell cycle regulators (such as cyclin D1, c-Myc and Wee1), oncogenes, and tumor suppressors, drive the circadian rhythm of body function and are responsible for the progression of diverse cellular process [8], [9], [10]. Growing evidence shows that disruption of circadian rhythm or defects in circadian genes are closely associated with an increased risk of various human diseases, including different types of malignancies [11], [12]. Epidemiological studies have revealed that loss of circadian homeostasis could be an independent cancer risk factor for breast [13], ovarian [14], prostate [15], lung [16], colorectal [17], and pancreatic cancers [18]. Due to the prevalence of chronic circadian disruption in modern lifestyle, the World Health Organization's International Agency for Research on Cancer (IARC) listed “shift-work that involves circadian disruption” as a probable carcinogen in 2007 [19].

Accumulating evidences have helped identify the importance of an intact circadian clock in controlling tissue-specific functions and cellular physiologies. Of all the known circadian genes, Bmal1(also known as Arntl or MOP3), which serves as a core component of the clockwork, is relatively poor understood in tumor biology compared with some other circadian genes such as Per1 and Per2 [20], [21]. Taniguchi et al. reported an epigenetic inactivation of the Bmal1 gene exists in hematologic malignancies [22]. Zeng et al. then found the tumor suppressor function of Bmal1 in colorectal cancer [23]; while Jung et al. revealed that Bmal1 could also inhibit tumor invasion [24]. However, Elshazley et al. reported its constitutive overexpression in malignant pleural mesothelioma [25]. Most recently, Jiang et al. investigated the role of Bmal1 in PDA and they found its significant inhibition on cell proliferation and marked induction of apoptosis and cell cycle arrest [26]. It is obviously observed that previous data were conflicting between different tumor types. Thus, in the present study, we examined the Bmal1expression in 87 cases of PDA samples and then correlated its level with pathological and prognostic factors to seek to determine the clinical significance of Bmal1 in PDA as well as its therapeutic potential.

Section snippets

Patient information and tissue samples

Eighty-seven diagnosed pancreatic ductal adenocarcinoma patients of all clinical and histological stages at Wuxi Second People's Hospital Affiliated to Nanjing Medical University between January 2008 and December 2014 were included in this study. Tumor tissues and paired non-cancerous tissues were obtained at following time points: 26 cases were between 10:00 and 12:00, 19 cases were between 12:00 and 14:00, 33 cases were between 14:00 and 16:00, and 9 cases were between 16:00 and 18:00. The

Characteristics of patients and tumors

A total of 87 PDA patients who received surgery resection between January 2008 and December 2014 were studied. Table 1 shows the clinicopathological characteristics of all the patients. The mean patient age was 62.1 years (SD, 13.5). The median follow-up duration was 31.8 months (range, 1 to 84). The samples included 13 cases of clinical stage I (14.9%), 31 cases of stage II (35.6%), 26 cases of stage III (29.9%), and 17 cases of stage IV (19.5%) tumors. Fifteen out of the 87 tumors (17.2%)

Discussion

Despite the disruption of circadian rhythms has been well linked to tumorigenesis in mammals and a considerable number of recent studies reporting abnormalities of circadian genes in various tumor types, it has not yet been comprehensively elucidated how the deregulated expression of clock genes is associated with the clinical features and survival outcomes in human PDA. As a core component of the molecular clock system, Bmal1 plays a key role in the maintenance of physiological homeostasis and

Conflicts of interest

The authors declare no conflicts of interest.

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