Original ArticlesDisruption of oncogenic liver-intestine cadherin (CDH17) drives apoptotic pancreatic cancer death
Introduction
Pancreatic cancer (PC) is the fourth-leading cause of cancer-related death accounting for about 3% of all cancers and about 7% of all cancer deaths [1,2]. The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with PC and 44,330 will die of this disease; by 2030, PC will be the second-leading cause of cancer death in the US [3]. Worldwide, PC accounts for more than 200,000 deaths every year with an average 5-year survival rate of <6% [4,5]. Surgical resection is possible only for a few early-stage patients (10–15%), but recurrence is common and the prognosis is very poor [6,7]. The lack of progress in prevention, early diagnosis, metastasis detection, and treatment underscores the need for increased efforts in PC research [8,9].
In 1994, liver–intestine cadherin, called cadherin-17 (CDH17) or human peptide transporter-1 (HPT-1), was characterized as a novel member of the cadherin superfamily. The cadherin superfamily is a type of cell adhesion molecules that play an important role in cell recognition, adhesion, and establishing cell-cell interaction [11,12]. Different from other members, an extracellular region of CDH17 contains seven cadherin domains [10]. As a component of the gastrointestinal tract, pancreatic CDH17 was shown to play a role in the morphological organization of liver and intestine. Disruption in expression or function of cadherins causes uncontrolled cell migration and proliferation during tumor development [13], therefore, CDH17 was also deemed to play a role in tumorigenesis and diagnosis [14]. In 2001, Grotzinger et al. first reported that CDH17 is a reliable and powerful marker molecule that can be used for early detection of gastric intestinal metaplasia and well-differentiated adenocarcinomas [15]. Their clinically relevant studies with human tumor tissue validated the positive relationship between CDH17 expression and gastric cancer progression [16]. In 2014, Dr. Wang et al. demonstrated that CDH17 is able to induce tumorigenesis and lymphatic metastasis in gastric cancer by activating NF-κB signaling pathways [17]. In 2017, Li et al. reported that silencing CDH17 with siRNAs suppresses gastric cancer growth in vitro and in vivo [18]. In 2009, another group demonstrated that RNA interference-mediated knockdown of CDH17 inhibited proliferation of both primary and highly metastatic hepatocellular carcinoma (HCC) in vitro and in vivo [19]. These studies reveal the tumorigenic effect of CDH17 and its clinical value in cancer diagnosis and treatment.
Although CDH17 has been demonstrated to promote growth in gastric and liver cancer for almost two decades [15], the role and mechanisms of action of CDH17 in other cancers including PC have yet to be elucidated. Using approaches including siRNA, shRNA, or CRISPR technologies, we have successfully conducted knockdown and knockout of CDH17 in Panc02-H7 cells and established the corresponding stable cell lines. Using these cells and approaches, we performed the loss-of-function studies to comprehensively investigate the role of CDH17 disruption in modulating PC development and the underlying mechanisms. The results gained from our in vitro and in vivo experiments suggest that CDH17 functions as an oncogene, promoting PC development by modulating cell survival and apoptosis signaling pathways.
Section snippets
Antibodies and plasmids
Antibodies against cleaved PARP, Akt, p-Akt (Thr308), Bcl-2, survivin, Bad, Bax, cytochrome C, cleaved caspase3, GAPDH, and Ki67 were purchased from Cell Signaling (Danvers, MA). Anti-mouse CDH17 antibody was purchased from R&D systems (Minneapolis, MN). Antibodies against human CDH17, β-actin, E-cadherin, N-cadherin, CDH16 were purchased from Abcam. All immunohistochemistry (IHC) reagents including ImmPRESS™ HRP anti-rabbit IgG (Peroxidase) (Cat#MP-7401), ImmPACT DAB peroxidase (HRP) substrate
Different levels of CDH17 expression in distinct PC cells and their derived orthotopic tumors
To investigate the role of CDH17 in PC tumor growth [15], we first examined CDH17 expression in different PC cell lines and their derived tumors. Using two mouse PC cell lines, including Panc02 and Panc02-H7 cells, we established their orthotopic murine model by injecting the cells into the head of the pancreas in wild-type C57BL/6 mice at a dose of 2.5 × 105 cells per mouse (Fig. 1A). At 17 days post inoculation, the average weight of tumors in each mouse induced by Panc02-H7 cells was
Discussion
To our knowledge, this is the first report describing CDH17 functions as a critical oncogenic gene modulating PC growth [27]. Using a loss-of-function strategy, we have demonstrated that CDH17 is necessary to maintain PC cell tumorigenic activity in vitro and to advance tumor growth in vivo. These findings significantly advance our understanding of CDH17 action in PC and provide a potential target to develop an anti-PC therapeutic strategy.
Using a loss-of-function strategy, we investigated how
Financial support
This project was supported by a startup fund from the University of Missouri (Guangfu Li, PI) and in part by the Priority Academic Program Development of Jiangsu Higher Education Institutions, Nanjing Medical University, China.
Conflicts of interest
There is none to declare.
References (37)
- et al.
Galectin-1-driven upregulation of SDF-1 in pancreatic stellate cells promotes pancreatic cancer metastasis
Cancer Lett.
(2017) - et al.
Advances in pancreatic cancer, IPMN and pancreatitis
Gastroenterology
(2018 Sep) - et al.
Estimates of cancer incidence and mortality in Europe in 2008
Eur. J. Cancer
(2010) - et al.
Targeted delivery of auristatin-modified toxins to pancreatic cancer using aptamers
Mol. Ther. Nucleic Acids
(2018) - et al.
Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model
J. Hepatol.
(2017) - et al.
HSP70 protein promotes survival of C6 and U87 glioma cells by inhibition of ATF5 degradation
J. Biol. Chem.
(2011) - et al.
BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner
J. Biol. Chem.
(2011) - et al.
A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum
Bba-Mol. Cell. Res.
(2014) - et al.
FDA-approved oligonucleotide therapies in 2017
Mol. Ther.
(2017) - et al.
Identification of liver-intestine cadherin in hepatocellular carcinoma--a potential disease marker
Biochem. Biophys. Res. Commun.
(2003)
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States
Cancer Res.
Cancer treatment and survivorship statistics
CA A Cancer J. Clin.
Centrosomal abnormalities in pancreatic cancer: molecular mechanisms and clinical implications
Anticancer Res.
Recent progress in pancreatic cancer
CA A Cancer J. Clin.
Development of a radiofrequency ablation platform in a clinically relevant murine model of hepatocellular cancer
Cancer Biol. Ther.
Liver-intestine cadherin - molecular-cloning and characterization of a novel Ca2+-dependent cell-adhesion molecule expressed in liver and intestine
J. Cell Biol.
Liver-intestine-cadherin is a sensitive marker of intestinal differentiation during Barrett's carcinogenesis
Dig. Dis. Sci.
Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/beta-catenin signaling
PLoS One
Cited by (22)
Integrated transcriptomics and proteomics data analysis identifies CDH17 as a key cell surface target in colorectal cancer
2023, Computational Biology and ChemistrySingle-cell RNA sequencing to characterize the response of pancreatic cancer to anti-PD-1 immunotherapy
2022, Translational OncologyCitation Excerpt :Data were analyzed using FlowJo software (Tree Star; https://www.flowjo.com/). Tumor tissue sections were prepared and fixed as previously described [19]. To conduct IHC staining, tissue sections were first de-paraffinized in xylene and rehydrated with various grades of alcohol (100, 95, 80, and 70%), then incubated with antigen unmasked with solution (H-3300, Vector Laboratories) on a steamer for 30 min.
YY1 inhibits the migration and invasion of pancreatic ductal adenocarcinoma by downregulating the FER/STAT3/MMP2 signaling pathway
2019, Cancer LettersCitation Excerpt :Pancreatic cancer is the fourth most common cause of cancer death and has a low early detection rate and high malignancy [1].
Data on the function of CDH17 in pancreatic cancer growth
2019, Data in BriefCitation Excerpt :Below is a brief description of the experimental methods used to acquire data in this paper. For a more detailed and thorough report, please refer to the related research article [1]. The mouse panc02-H7 cell line was a gift from the MD Anderson Cancer Center.
- 1
Xinjian Liu & Yue Huang contributed equally to this manuscript as first authors.