Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois, Chicago, Illinois, United States of America.
University of Illinois College of Medicine, Chicago, Illinois, United States of America.
PLoS One. 2019 Mar 21;14(3):e0211711. doi: 10.1371/journal.pone.0211711. eCollection 2019.
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.
目前用于治疗胰腺导管腺癌 (PDAC) 的疗法仅能在一定程度上延长生存期，且可能具有高度毒性。深入了解调控该疾病的分子机制对于确定新的药物靶点和开发更有效的疗法至关重要。L6 蛋白家族已被证实是多种癌症中肿瘤生长和转移的正向调控因子。然而，关于 L6 家族成员 TM4SF18 的研究却知之甚少。我们研究了 TM4SF18 蛋白在正常胰腺组织和 PDAC 组织中的表达和定位。通过免疫组化（IHC）和 Western blot 分析，我们首次证明 TM4SF18 在 PDAC 肿瘤上皮中高度表达。此外，我们发现 TM4SF18 在正常胰腺实质组织中表达，在正常导管中表达较弱。尽管在正常导管中表达水平较低，但我们观察到 TM4SF18 在癌前导管和肿瘤上皮中的水平升高。为了研究 TM4SF18 在 PDAC 中的功能作用，我们构建了稳定表达诱导型 shRNA 的胰腺癌细胞系。通过 MTT 测定法，TM4SF18 蛋白的敲低导致 Capan-1 细胞生长显著减少，表明该分子是 PDAC 的一种新型调控因子。TM4SF18 基因在小鼠或大鼠中没有同源基因，这促使我们寻求其他体内实验模型。通过 IHC 和 Western blot 分析，我们在猪 PDAC 模型中证实了 TM4SF18 的表达，因此我们建立了一个替代模型来研究该基因。TM4SF18 是一种有前途的新型胰腺癌生物标志物和治疗靶点。
