Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a very low median survival rate. The lack of early sensitive diagnostic markers is one of the main causes of PDAC-associated lethality. Therefore, to identify novel pancreatic cancer biomarkers that can facilitate early diagnosis and also help in the development of effective therapeutics, we developed RNA aptamers targeting pancreatic cancer by Cell-systematic evolution of ligands by exponential enrichment (SELEX) approach. Using a selection strategy that could generate aptamers for 2 pancreatic cancer cell lines in one selection scheme, we identified an aptamer SQ-2 that could recognize pancreatic cancer cells with high specificity. Next, by applying 2 alternative approaches: (i) aptamer-based target pull-down and (ii) genome-wide microarray-based identification of differentially expressed mRNAs in aptamer-positive and -negative cells, we identified alkaline phosphatase placental-like 2 (ALPPL-2), an oncofetal protein, as the target of SQ-2. ALPPL-2 was found to be ectopically expressed in many pancreatic cancer cell lines at both mRNA and protein levels. RNA interference-mediated ALPPL-2 knockdown identified novel tumor-associated functions of this protein in pancreatic cancer cell growth and invasion. In addition, the aptamer-mediated identification of ALPPL-2 on the cell surface and cell secretions of pancreatic cancer cells supports its potential use in the serum- and membrane-based diagnosis of PDAC.
Highlights
Pancreatic adenocarcinoma is one of the few cancers for which the survival rate has not improved in the last 40 years
Placental (ALPP) and placental like (ALPPL-2) alkaline phosphatases seem to be associated with the malignancy of germ cells and some nongerm cell tissues
alkaline phosphatase placental-like 2 (ALPPL-2) has been found to be overexpressed in testicular cancers and seminoma of the testis [42, 43]
Summary
Pancreatic adenocarcinoma is one of the few cancers for which the survival rate has not improved in the last 40 years. Around 90% of these pancreatic tumors are pancreatic ductal adenocarcinomas (PDAC; ref 1). While complete surgical removal is the only curative option for this disease, only 15% to 20% of these tumors are resectable at the time of diagnosis [2]. The lack of early diagnostic markers poses a major problem for timely detection [3, 4]. There is an urgent need for the development of novel pancreatic cancer biomarkers that can facilitate early diagnosis and aid in the development of effective therapeutics. Cancer cell–specific membrane proteins are considered to be the most appropriate biomarkers because they are often shed in body fluids in detectable amounts.
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