Abstract
Current therapies for pancreatic ductal adenocarcinoma (PDAC) only modestly impact survival and can be highly toxic. A greater understanding of the molecules regulating this disease is critical for identifying new drug targets and developing more effective therapies. The L6 family of proteins are known to be positive regulators of tumor growth and metastasis among various cancers. However, little is known about the L6 family member TM4SF18. We investigated the expression and localization of the TM4SF18 protein in normal human pancreas and in PDAC tissue. Utilizing immunohistochemistry (IHC) and western blot analysis, our studies for the first time demonstrate that TM4SF18 is highly expressed in PDAC tumor epithelium. Furthermore, we identified TM4SF18 to be expressed in normal acinar tissue and weakly expressed in normal ducts. Although there is minimal expression in normal ducts, we observed increased TM4SF18 levels in preneoplastic ducts and tumor epithelium. To investigate a functional role of TM4SF18 in PDAC we developed stably-expressing inducible shRNA pancreatic cancer cell lines. Knockdown of the TM4SF18 protein led to a significant decrease in Capan-1 cell growth as measured by the MTT assay, demonstrating this molecule to be a novel regulator of PDAC. Uniquely there is no ortholog of the TM4SF18 gene in mouse or rat prompting us to seek other in vivo experimental models. Using IHC and western blot analysis, expression of TM4SF18 was confirmed in the porcine PDAC model, thus we establish an alternative model to investigate this gene. TM4SF18 represents a promising novel biomarker and therapeutic target for pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma cancer (PDAC) is one of the deadliest cancers predicted to be the second-largest cause of cancer-related death by 2020 [1]
Human Pancreatic Ductal Epithelial (HPDE) cells are an immortalized cell-line derived from primary cultures of normal ductal epithelial cells and are grown in Keratinocyte serumfree (KSF) medium supplemented with 50 mg/ml bovine pituitary extract (BPE) and 5 ng/ml epidermal growth factor (EGF)
To our knowledge we provide the first evidence that TM4SF18 is expressed in normal and pancreatic cancer tissue including acinar tissue, pre-neoplastic ductal lesions, and tumor epithelium
Summary
Pancreatic ductal adenocarcinoma cancer (PDAC) is one of the deadliest cancers predicted to be the second-largest cause of cancer-related death by 2020 [1]. TM4SF18 regulates pancreatic cancer cell growth rate is at 9% mainly due to poor detection methods and lack of therapeutic options [2]. The L6 superfamily consists of six members (TM4SF-1, -4, -5, -18, -19, and -20) characterized to have four-transmembrane domains [3]. Members of the L6 family were originally classified as tetraspanins. Members of L6 superfamily are known to play vital roles in various functions in tumorigenesis including invasion, motility, EMT, adhesion, and cell growth [4,5,6,7,8,9,10]. TM4SF1 is one well-studied L6 family member found to be over-expressed in pancreatic cancer and plays a role in pancreatic cancer cell invasion and chemoresistance [10, 11]. TM4SF18 is highly homologous to TM4SF1 but has yet to be studied in any aspect of cancer biology
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