MicroRNAs as Indicators and Predictors of Pancreatic Adenocarcinoma

Christian Prinz and David Weber

Helios Klinikum Wuppertal, Medizinische Klinik, University of Witten, Germany

*Corresponding Author:
Christian Prinz
Lehrstuhl Innere Medizin 1
University of Witten, Heusnerstrasse 40
D-42283 Wuppertal, Germany
Tel 0049-202-896-2243
E-mail [email protected]

Received Date: April 01st, 2016; Accepted Date: July 06th, 2016

 
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Abstract

Chronic pancreatitis is a chronic inflammatory disorder, triggered by various factors. Several factors increase the risk of the development of pancreatic adenocarcinoma, including age, smoking, and chronic alcohol consumption. Predictors for cancer development are currently not available in the stage of chronic pancreatitis; and technical procedures such as endoscopic ultrasound or MRI scanning techniques are often hampered by a low specificity of cancer prediction. Thus, pancreatic cancer is often diagnosed at advanced stages, and chemotherapy does not improve the outcome dramatically. A reliable test in blood, tumor or bile would help to detect the tumors at earlier stage. Most interestingly, a new predictive parameter has recently evolved since MicroRNAs have been associated with cancer development and progression, and recent scientific evidence suggests that MicroRNAs can be regarded as “tumor markers” since several molecules are expressed at high levels in the tumors themselves throughout different patient groups. MicroRNAs expression profiles even seems to classify human gastrointestinal cancer better that MicroRNAs –protein expression profiles. Among the various molecules, miR- 21, miR-34a, miR-198, mir-155 and miR-217 have been shown to be highly specific as biomarkers differentiating between chronic pancreatitis and pancreatic ductal adenocarcinoma. Also, MicroRNAs-196a and -196b have been described as potential biomarkers for the early detection of familial pancreatic cancer. Pilot studies now aim to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select MicroRNAs in plasma and bile, not only to predict cancer development but also to understand molecular basis of cancer pr ogression.

Keywords

MicroRNAs; Pancreatic Neoplasms

INTRODUCTION

Prognosis and treatment options of pancreatic cancer are still limited because pancreatic cancer is often diagnosed in an advanced tumor stage. According to the American cancer society, only 9% of all pancreatic cancers are diagnosed in a localized tumor stage, whereas 56% of patients had distant metastasis at diagnosis stage [1]. Therefore, treatment is often restricted to palliative regimes. Regardless of the underlying tumor stage, overall 5 years survival is about 6% [1]. In general tumor stage of pancreatic cancer is categorized into surgically resectable, locally advanced (LA) and metastatic pancreatic cancer. R0 resection is considered to be the only potentially curative approach in pancreatic cancer. However, due to non-detectable distant metastasis and a high rate of local recurrences, the 5 years survival rate after R0 resection is about 20% [1]. Although pancreatic cancer is still lethal in most cases, new, encouraging diagnostic new molecular tool have been established in the last years, which will be presented and discussed in the following.

Current Diagnostic Approaches in Pancreatic Cancer

Painless jaundice is a characteristic sign of pancreatic cancer, but it is almost always associated with an advanced tumor stage. Characteristic early symptoms are missing in pancreatic cancer, some patients have complained about chronic abdominal pain but did not get accurate diagnosis. Interestingly, onset of diabetes mellitus can be an early sign of pancreatic cancer. A meta-analysis of 88 studies [2] found a strong association between a recently diagnosed diabetes mellitus and pancreatic cancer. These data suggest that patients with new-onset DM should be screened for pancreatic cancer. Until quite recently, routine preoperative biliary drainage was performed in patient undergoing surgery. However, van der Gaag et al. [3] compared in a multicenter randomized trail routine preoperative biliary drainage versus surgery alone. This landmarks study clearly showed that rates of serious complications were significantly higher in the biliarydrainage group than in the early surgery group [74% vs. 39% (0.54; 95% CI, 0.41 to 0.71)]. Therefore, preoperative biliary drainage in patients undergoing surgery is currently only recommended in patients with cholangitis. Furthermore, there is no need to perform a biopsy for histological proof, unless patients are undergoing a chemotherapeutic treatment or imaging findings are not clear. The reason for this reserved attitude towards histological proof is the fear of tumor cell dissemination along the needle track. However, this fear appears to be unfounded in practice. A previously published study [4] analysed the long-term outcomes of patients with resected pancreatic cancer and preoperative Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The authors found that preoperative EUS-FNA was not associated with increased risk of mortality and concluded that EUS-FNA is a safe approach to assess the dignity of suspicious pancreatic lesions. Furthermore, EUS FNA testing new molecules could be become a safe standard, and new parameters will be discussed in the following.

MicroRNAs: New Molecular Tool in Pancreatic Adenocarcinoma

An new and interesting predictive parameter has recently evolved since MicroRNAs have been associated with cancer development and progression, underlining a potential for predictive markers [5, 6, 7].

MicroRNAs (MicroRNAss) are non-protein coding ~22 nucleotide RNAs that induce translational repression and/ or degradation of their MicroRNAs targets. MicroRNAs are small noncoding RNAs that are cleaved from 70-100 nucleotide haiprins pre-MicroRNAs precursors in the cytoplasm by RNAase III Dicer into their mature form of 22 nt. Single stranded MicroRNAs bind messenger RNA of potentially hundreds of genes at the 3 untranslated region with perfect of near perfect complementarity, resulting in degradation or inhibition of the target messenger RNA. In humans, aberrant expression of MicroRNAs contributed to carcinogenesis by promoting the expression of proto oncogenes or by inhibition of tumor suppressor genes. MicroRNAs, in complex with AGO protein, uses seed sequences near the 5’ end to base pair with a target MicroRNAs, thereby inducing de-adenylation and decay or translational regulation [8]. A growing body of evidence not only suggests that bacterial and viral infection of mammalian and plant cells can modulate MicroRNAs expression, but recent data also suggest a key role of these molecules in cancer development and progression [8].

MicroRNAs expression profiles seem to classify human gastrointestinal cancer better that MicroRNAs–protein expression profiles, as demonstrated recently in a new approach [9]. The recent work [9] used a bead-based flow cytometric MicroRNAs expression profiling method to present a systematic expression analysis of 217 mammalian MicroRNAss from 334 samples, including multiple human cancers. The group observed a general down-regulation of MicroRNAs in tumours compared with normal tissues. Furthermore, they were able to successfully classify poorly differentiated tumours using MicroRNAs expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. The report suggested that one of the key roles of MicroRNAs expression is the posttranscriptional silencing of targeted genes, the enhancement of proteins being translated, or the prevention of apoptosis by binding to promoter units involved in cell cycle regulation, and these findings highlight the potential of MicroRNAs profiling in cancer diagnosis.

MicroRNA Expression in Chronic Pancreatitis and Pancreatic Cancer

In particular, diagnosis of pancreatitic cancer in patients with chronic pancreatitis is challenging, because transition of a chronic inflammatory induced tumor mass into a malignant process is blurred and difficult to distinguish by morphological imaging and histopathological procedures [10]. The typical biology of pancreatic ductal adenocarcinoma is one of aggressive local invasion, early metastasis, and resistance to chemotherapy and radiation. Known genetic mutations include TP53, KRAS, CDKN2A, and SMAD 4, but these factors do not account for aggressive behavior.

In a comprehensive work published by Bloomston et al. [11], global expression patterns in patients with chronic pancreatitis and pancreatic ductal adenocarcinoma were identified, and this works described a more than 95% accuracy of seven MicroRNAs molecules: miR-99, miR- 100, miR100-1/2, miR-125a, miR-125b, miR-199a1 and miR199-a2. Furthermore, expression of mir196-a-2 had a significant impact on survival. Some the molecules that may have an interesting role for survival are known as hypoxia related MicroRNAs. Data were confirmed in further studies of the same group in later years [12, 13, 14].

This work also described the difference of the MicroRNAs content between the two different groups. Six different MicroRNAs were differentially expressed at more than 2-fold difference: miR-21, miR-148a/b, miR- 155, miR-181a/b/c/d, miR-221 and miR-275 [11]. Most notably, miR-21 and mir-155 were uniquely overexpressed in pancreatic cancer vs normal pancreas and chronic pancreatitis [11]. Mir-21 has been suggested to play an important role in preventing apoptosis, thus functioning as a proto oncogene. The most highly expressed MicroRNAs in pancreatic cancer was miR-21, when comparing cancer with chronic pancreatitis. MicroRNAs 221 is important in thyroid cancer, and suggested to play a role in angiogenesis. Far fewer molecules were downregulated in this study, most notable mir-375 normally found in pancreatic islets.

As illustrated in table 1, numerous studies have been performed regarding the functional and biological role of MicroRNAs in pancreatic adenocarcinoma, and results are shown in Table 1.

image

In most recent works, Le Large et al. have pointed out that circulation MicroRNAs may be used as diagnostic biomarkers for pancreatic cancer, and the circulating MicroRNAs molecules can be determined in blood as diagnostic biomarkers [15, 16]. Interestingly, label-free nanoplasmonic-based short noncoding RNA Sensing at attomolar concentrations seem to allow for quantitative and highly specific assay of MicroRNA-10b in biological fluids and circulating exosomes [17]. Also, MicroRNAs in stool samples have been described as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer [18]. Circulating MicroRNAs in Pancreatic Juice as Candidate Biomarkers of Pancreatic Cancer [19]. A MicroRNA meta-signature for pancreatic ductal adenocarcinoma [20].

Recent studies using Roc analysis (ROC: receiver operating characteristics) indicated that MicroRNAss could be extracted and detected from pancreatic juice and stool efficiently and reproducibly, and that MiR- 21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC [18]. The data using a combination of MicroRNAss were obtained through processing the original expression data of miR- 21, miR-155 and miR-216 by logistic regression analysis. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool MicroRNAss in PDAC patients; and these data indicated that a combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.77-0.96) and a better balance of sensitivity and specificity (83.3% vs. 83.3%). Onviously, miR-21, miR- 155 and miR-216 in stool seemed to have the potential of becoming biomarkers for screening PDAC.

Recent reports further support the view that among the various molecules, especially miR-21, miR-34a, miR- 198 and miR-217 can be regarded as highly specific as diagnostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma [21]. In this work, expression of the microRNAs miR-198, miR-217, miR- 21 and miR-34a was determined in normal tissue, tissue of chronic pancreatitis and pancreatic adenocarcinoma (PDAC). While the expression of miR-198 increased from normal tissue to CP and PDAC, the expression of miR- 217 decreased in a opposite fashion. The other two only showed specific expression in tumor tissue. Thus, MiR- 21 and miR-34a seem to be excellent tissue biomarkers differentiating chronic pancreatitis from PDAC.

Also, MicroRNA-196a and 196b were confirmed as potential biomarkers for the early detection of familial pancreatic cancer [22]. Interestingly, a pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select MicroRNAs in plasma and bile, which is currently under further investigation [23, 24].

CONCLUSION

MicroRNAs (MicroRNAss) are non-protein coding ~22 nucleotide RNAs that induce translational repression and/ or degradation of their mRNA targets. In surgical specimens obtained from pancreatic tumor tissue as well as normal or chronically inflamed pancreatic tissue, miR-21, miR-34a, miR-155, miR-196-a/b, and miR-198 have been shown to be highly specific biomarkers differentiating between chronic pancreatitis and pancreatic ductal adenocarcinoma. Pilot studies now aim to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select MicroRNAs in plasma and bile. Furthermore, tumor specimens obtained through endoscopically guided fine needle aspiration could present a new tool to test the presence of such MicroRNAs molecules, allowing for new cancer markers, not only to predict cancer presence but also to understand molecular basis of cancer progression.

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

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