Gene Summary

Gene:CDH17; cadherin 17
Aliases: HPT1, CDH16, HPT-1
Summary:This gene is a member of the cadherin superfamily, genes encoding calcium-dependent, membrane-associated glycoproteins. The encoded protein is cadherin-like, consisting of an extracellular region, containing 7 cadherin domains, and a transmembrane region but lacking the conserved cytoplasmic domain. The protein is a component of the gastrointestinal tract and pancreatic ducts, acting as an intestinal proton-dependent peptide transporter in the first step in oral absorption of many medically important peptide-based drugs. The protein may also play a role in the morphological organization of liver and intestine. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CDH17 (cancer-related)

van Huizen NA, Coebergh van den Braak RRJ, Doukas M, et al.
Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue.
J Biol Chem. 2019; 294(1):281-289 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Changes to extracellular matrix (ECM) structures are linked to tumor cell proliferation and metastasis. We previously reported that naturally occurring peptides of collagen type I are elevated in urine of patients with colorectal liver metastasis (CRLM). In the present study, we took an MS-based proteomic approach to identify specific collagen types that are up-regulated in CRLM tissues compared with healthy, adjacent liver tissues from the same patients. We found that 19 of 22 collagen-α chains are significantly up-regulated (

Tian X, Han Z, Zhu Q, et al.
Silencing of cadherin-17 enhances apoptosis and inhibits autophagy in colorectal cancer cells.
Biomed Pharmacother. 2018; 108:331-337 [PubMed] Related Publications
Cadherin-17 (CDH17), a structurally unique member of the non-classical cadherin family, is associated with poor survival, cell proliferation, and metastasis in colorectal cancer. However, the role of CDH17 in the apoptosis and autophagy of colorectal cancer cells remains unclear. Here, we aimed to investigate the effect of CDH17 knockdown on autophagy and apoptosis in colorectal cancer cells. We inhibited CDH17 expression in KM12SM and KM12C colorectal cancer cells by RNA interference and found that silencing of CDH17 significantly inhibited cell viability and increased apoptosis in KM12SM and KM12C cells. In addition, silencing of CDH17 significantly increased the expression of cleaved caspase-3 and Bax and decreased the expression of Bcl-2. Concurrently, silencing of CDH17 significantly inhibited the conversion of LC3-I to LC3-II and decreased the formation of LC3

Suspitsin E, Yanus G, Imyanitov E
Diagnosis for carcinoma of unknown primary site with the aid of simple PCR tests: a single-center experience.
Neoplasma. 2018; 65(3):461-468 [PubMed] Related Publications
This study was aimed to incorporate PCR testing in the determination of organ/tissue origin for cancers of unknown primary site (CUP). We developed a PCR panel consisting of 7 expression markers (CDX2, CDH17, SPB, UGRP, MAM, LPB, TG) and 2 genes frequently mutated in cancer (KRAS and BRAF). The expression tests were intentionally interpreted in a non-quantitative way, i.e. classified tumors either as positive or negative expressors. While applying these tests to 135 cancers belonging to 8 common types of adenocarcinomas (AdCa), we observed that this panel was capable to clearly discriminate between gastrointestinal vs. female reproductive tract vs. lung vs. thyroid tumors in 112 (83%) of cases and provided suggestive clues to correct diagnosis in 20 (15%) of instances. We further assessed the performance of this panel, coupled with the occasional use of 2 additional mutation tests (somatic: EGFR; germ-line: BRCA1), in the real diagnostic setting. The PCR analysis of 20 consecutive CUP with known IHC status turned out to be clinically useful in 19 (95%) cases, with 16 (80%) instances of resolving the existing controversy and 3 (15%) cases of providing valuable confirmation to suspected diagnosis. PCR testing of 20 consecutive CUP with unknown IHC status succeeded to establish tumor organ/tissue origin in 15 (75%) instances and provided suggestive clues to the diagnosis in 3 (15%) patients. We conclude that simple non-expensive laboratory-developed PCR assays may aid CUP diagnosis in a significant proportion of cases.

Jiang XJ, Lin J, Cai QH, et al.
CDH17 alters MMP-2 expression via canonical NF-κB signalling in human gastric cancer.
Gene. 2019; 682:92-100 [PubMed] Related Publications
Gastric cancer (GC), one of the most common cancers of the digestive system, results in high morbidity and mortality, but the molecular mechanisms underlying GC remain largely unknown. Cadherin-17 (CDH17) is a nonclassical member of the cadherin (CDH) superfamily of calcium-dependent proteins. Despite recent advances in the understanding of CDH17 biology, the mechanism of CDH17 in GC proliferation, migration, and invasion has not been extensively studied. In the present study, we observed that CDH17 expression was increased in GC tissues compared with para-carcinoma tissues and was correlated with lymph node metastasis and the AJCC stage. Additionally, a significant correlation was found between CDH17 protein expression and the number of blood and lymph vessels in GC tissues. Furthermore, in vitro suppression of CDH17 expression using short-interfering RNA (siRNA) decreased AGS cell proliferation, migration and invasion. Conversely, overexpression of CDH17 through plasmid transfection enhanced the malignant activity of AGS cells. Moreover, CDH17 increased the matrix metallopeptidase 2 (MMP-2) levels via the canonical nuclear factor-kappaB (NF-κB) pathway. Our findings offer new insights into the mechanism of the CDH17/NF-κB/MMP-2 axis, and the associated signalling pathways might represent novel targets for the treatment of GC.

Sadowski SM, Pusztaszeri M, Brulhart-Meynet MC, et al.
Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism.
J Clin Endocrinol Metab. 2018; 103(6):2189-2198 [PubMed] Related Publications
Context: Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).
Objective: To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.
Design: Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.
Results: The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.
Conclusions: The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.

Zhang C, Shen Y, Wang J, et al.
Identification of key pathways and genes in Barrett's esophagus using integrated bioinformatics methods.
Mol Med Rep. 2018; 17(2):3069-3077 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Barrett's esophagus (BE) is a premalignant lesion of esophageal adenocarcinoma. The aim of the present study was to investigate the possible mechanisms and biomarkers of BE. To identify the differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) in BE, the miRNA expression profile GSE20099 and the gene expression profiles GSE26886, GSE13083 and GSE34619 were obtained from the Gene Expression Omnibus (GEO) database. DEGs and DEmiRNAs were screened for using the GEO2R tool. Using DAVID, functional and pathway enrichment analysis was performed to explore the biological function of identified DEGs. The protein‑protein interaction (PPI) network was detected using STRING and constructed by Cytoscape software. Furthermore, targets of identified DEmiRNAs were predicted by the miRecords database, then integrated with the identified DEGs to obtain key genes involved in BE. In total, 311 DEGs were identified. These genes were significantly enriched in the pancreatic secretion, metabolic pathways and cytochrome P450 drug metabolism pathways. In the PPI network, 16 hub genes, including keratin 16, cystic fibrosis transmembrane conductance regulator, involucrin, protein kinase C α and cadherin 17 were identified. Following integration of the predicted target genes of DEmiRNAs with DEGs, three key BE genes were identified: PRKCA, CDH17 and epiregulin. In conclusion, a comprehensive bioinformatics analysis of identified DEGs and DEmiRNAs was performed to elucidate potential pathways and biomarkers involved in the development of BE.

Liu M, Han Z, Zhu QX, et al.
Downregulation of liver-intestine cadherin enhances cisplatin-induced apoptosis in human gastric cancer BGC823 cells.
Cancer Gene Ther. 2018; 25(1-2):1-9 [PubMed] Related Publications
Gastric cancer is the fourth most common type of cancer. Liver-intestine cadherin (CDH17) has been found to be involved in the proliferation and apoptosis of gastric cancer cells. Cisplatin is one of the most widely used antineoplastic agents in the treatment of solid tumor and hematological malignancies. However, the mechanism of enhancing cisplatin-inducing effects on human gastric cancer BGC823 cells by blocking CDH17 gene, both in vitro and in vivo, remains to be clarified. In this study, we investigated the signaling pathway by which cisplatin induces apoptosis by blocking CDH17 gene in gastric cancer BGC823 cells. Our results indicate that down-expression of CDH17 gene can enhance apoptosis-inducing effects of cisplatin on human gastric cancer BGC823 cells. The expression levels of Bax and Cyt-c proteins were upregulated, but the expression levels of Bcl-2 and Bcl-xL proteins were downregulated by blocking CDH17 gene in gastric cancer BGC823 cells after treatment with cisplatin. Moreover, down-expression of CDH17 enhanced the efficacy of cisplatin-induced inhibition of tumor growth in nude mice via apoptosis induction. Down-expression of CDH17 gene can significantly improve apoptosis-inducing effects of cisplatin in vitro and in vivo, which is a new strategy to improve chemotherapeutic effects on gastric cancer.

Shek FH, Luo R, Lam BYH, et al.
Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma.
Cell Oncol (Dordr). 2017; 40(5):443-456 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients.
RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/β-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in β-catenin expression (a core component of the CDH17/β-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway.
CONCLUSIONS: Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.

Tian X, Liu M, Zhu Q, et al.
Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells.
Expert Rev Anticancer Ther. 2017; 17(9):857-863 [PubMed] Related Publications
BACKGROUND: The aim of the present study was to explore the signaling pathway of noscapine which induces apoptosis by blocking liver-intestine cadherin (CDH17) gene in colon cancer SW480 cells.
METHODS: Human colon cancer SW480 cells were transfected with CDH17 interference vector and treatment with 10 µmol/L noscapine. The proliferation and apoptosis of SW480 cells were detected by MTT assay and AnnexinV-FITC/PI flow cytometry kit (BD), respectively. Cell invasion were assessed by transwell assays. Apoptosis related proteins (Cyt-c, Bax, Bcl-2 and Bcl-xL) levels were evaluated by western blot.
RESULTS: Compared to the noscapine group, the proliferation was decreased significantly and the apoptosis was increased significantly in SW480 cells of the siCDH17+noscapine group. Cyt-c and Bax protein levels in siCDH17+noscapine group was higher than that of the noscapine group, but Bcl-2 and Bcl-xL protein levels in siCDH17+noscapine group were lower than that of the noscapine group. Moreover, up-expression of CDH17 inhibited the efficacy of noscapine-induced apoptosis in SW480 cells.
CONCLUSIONS: We inferred that down-expression of extrinsic CDH17 gene can conspicuously promote apoptosis-inducing effects of noscapine on human colon cancer SW480 cells, which is a novel strategy to improve chemotherapeutic effects on colon cancer.

Qu LP, Zhong YM, Zheng Z, Zhao RX
CDH17 is a downstream effector of HOXA13 in modulating the Wnt/β-catenin signaling pathway in gastric cancer.
Eur Rev Med Pharmacol Sci. 2017; 21(6):1234-1241 [PubMed] Related Publications
OBJECTIVE: In this study, we investigated the mechanism underlying co-upregulation of HOXA13 and CDH17 in gastric cancer, the signaling pathway in which HOXA13 and CDH17 involve in and their functional role in gastric cancer cells.
MATERIALS AND METHODS: Relevant microarrays investigated the dysregulated genes in gastric cancer tissues were searched in ArrayExpress. The co-expression of HOXA13 and CDH17 was analyzed in the gastric cancer patient cohort in TCGA database using cBioportal and UCSC Xena. The regulative effect of HOXA13 on CDH17 expression was examined by dual luciferase assay. The involvement of HOXA13 and CDH17 in the Wnt/beta-catenin signaling pathway was assessed by Western blotting. The functional role of HOXA13 and CDH17 in gastric cancer cells were studied by CCK-8 assay of cell growth, Transwell assay of cell invasion and flow cytometry of active caspase-3.
RESULTS: HOXA13 and CDH17 expression are upregulated and are highly correlated in gastric cancer tissues. HOXA13 overexpression significantly increased CDH17 mRNA and protein expression and also significantly increased the transcription activity of the luciferase reporter with integrate HOXA13 binding sites. HOXA13 shRNA and CDH17 shRNA had similar effect on reducing the expression of beta-catenin, while shCDH17 abrogated HOXA13 induced upregulation of beta-catenin. HOXA13 shRNA and CDH17 shRNA decreased cell proliferation and invasion and increased cell apoptosis in SGC-7901 cells.
CONCLUSIONS: HOXA13 can elevate CDH17 transcription via binding to its promoter. CDH17 is a downstream effector of HOXA13 in modulating the Wnt/beta-catenin signaling pathway in gastric cancer cells. Both HOXA13 shRNA and CDH17 shRNA can decrease gastric cancer cell proliferation and invasion and increase their apoptosis.

Li R, Yang HQ, Xi HL, et al.
Inhibition of CDH17 gene expression via RNA interference reduces proliferation and apoptosis of human MKN28 gastric cancer cells.
Int J Oncol. 2017; 50(1):15-22 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Gastric cancer is the fourth most common type of cancer and the second cause of cancer‑related mortalities worldwide despite the use of multimodal therapy. Cadherins are transmembrane glycoproteins that are involved in tumorigenesis. CDH17 has been found to be over‑expressed in gastric cancer and its overexpression was associated with lymph node metastasis and tumor‑node‑metastasis stage of the patients, yet the exact role and molecular mechanism of CDH17 in gastric cancer have not been determined. Using a lentiviral system as a delivery mediator of RNA interference, we found that inhibition of CDH17 can lead to reduce proliferation and increase apoptosis of gastric cancer cell line MKN28 in vitro and significantly diminish their tumorigenicity in vivo. Our results of the present study suggest that CDH17 may be a promising candidate for the therapeutic targeting of gastric cancer.

Picco G, Petti C, Sassi F, et al.
Efficacy of NEDD8 Pathway Inhibition in Preclinical Models of Poorly Differentiated, Clinically Aggressive Colorectal Cancer.
J Natl Cancer Inst. 2017; 109(2) [PubMed] Related Publications
Background: The NEDD8 conjugation pathway modulates the ubiquitination and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of response predictors are still missing.
Methods: We investigated in vitro sensitivity to pevonedistat in 122 colorectal cancer (CRC) cell lines by an ATP-based proliferation assay and evaluated apoptosis and DNA content by flow cytometry. Associations between pevonedistat sensitivity and CRC molecular features were assessed by Student's t test. A 184-gene transcriptional predictor was generated in cell lines and applied to 87 metastatic CRC samples for which patient-derived xenografts (PDXs) were available. In vivo reponse to pevonedistat was assessed in PDX models (≥5 mice per group). All statistical tests were two-sided.
Results: Sixteen (13.1%) cell lines displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block, and increased apoptosis. Pevonedistat sensitivity did not statistically significantly correlate with microsatellite instability or mutations in KRAS or BRAF and was functionally associated with low EGFR pathway activity. While ineffective on predicted resistant PDXs, in vivo administration of pevonedistat statistically significantly impaired growth of five out of six predicted sensitive models (P < .01). In samples from CRC patients, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery (hazard ratio [HR] = 2.49, 95% confidence interval [CI] = 1.34 to 4.62, P = .003) and early progression under cetuximab treatment (HR = 3.59, 95% CI = 1.60 to 8.04, P < .001). Histological and immunohistochemical analyses revealed that the pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma.
Conclusions: These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective treatment for poorly differentiated, clinically aggressive CRC.

Matsusaka K, Ushiku T, Urabe M, et al.
Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer.
Oncotarget. 2016; 7(39):64168-64181 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Patients with gastric cancer typically face gastrectomies even when few or no nodal metastases are reported. Current procedures poorly predict lymphatic metastases; thus, evaluation of target molecules expressed on cancer cell membranes is necessary for in vivo detection. However, marker development is limited by the intratumoral heterogeneity of gastric cancer cells. In this study, multiple gene expression arrays of 42 systemic normal tissue samples and 56 gastric cancer samples were used to investigate two adhesion molecules, cadherin 17 (CDH17) and claudin 18 (CLDN18), which are intestinal and gastric markers, respectively. Expression of CDH17 and CLDN18 was partially redundant, but overlapped in 50 of 56 cases (89.3%). Tissue microarrays constructed using primary lesions and nodal metastases of 106 advanced gastric cancers revealed CDH17 and CLDN18 expression in 98 positive cases of 106 (92%). Hierarchical clustering classified gastric cancers into three subgroups, CDH17(++)/CLDN18(+/-), CDH17(++)/CLDN18(++) or CDH17(+)/CLDN18(+), and CDH17(-)/CLDN18(++/+/-). Whole tissue sections displayed strong, homogeneous staining for CDH17 and CLDN18. Together, these results indicate that CDH17 and CLDN18 are useful target molecules; moreover, their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity.

Onstenk W, Sieuwerts AM, Mostert B, et al.
Molecular characteristics of circulating tumor cells resemble the liver metastasis more closely than the primary tumor in metastatic colorectal cancer.
Oncotarget. 2016; 7(37):59058-59069 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: CTCs are a promising alternative for metastatic tissue biopsies for use in precision medicine approaches. We investigated to what extent the molecular characteristics of circulating tumor cells (CTCs) resemble the liver metastasis and/or the primary tumor from patients with metastatic colorectal cancer (mCRC).
RESULTS: The CTC profiles were concordant with the liver metastasis in 17/23 patients (74%) and with the primary tumor in 13 patients (57%). The CTCs better resembled the liver metastasis in 13 patients (57%), and the primary tumor in five patients (22%). The strength of the correlations was not associated with clinical parameters. Nine genes (CDH1, CDH17, CDX1, CEACAM5, FABP1, FCGBP, IGFBP3, IGFBP4, and MAPT) displayed significant differential expressions, all of which were downregulated, in CTCs compared to the tissues in the 23 patients.
PATIENTS AND METHODS: Patients were retrospectively selected from a prospective study. Using the CellSearch System, CTCs were enumerated and isolated just prior to liver metastasectomy. A panel of 25 CTC-specific genes was measured by RT-qPCR in matching CTCs, primary tumors, and liver metastases. Spearman correlation coefficients were calculated and considered as continuous variables with r=1 representing absolute concordance and r=-1 representing absolute discordance. A cut-off of r>0.1 was applied in order to consider profiles to be concordant.
CONCLUSIONS: In the majority of the patients, CTCs reflected the molecular characteristics of metastatic cells better than the primary tumors. Genes involved in cell adhesion and epithelial-to-mesenchymal transition were downregulated in the CTCs. Our results support the use of CTC characterization as a liquid biopsy for precision medicine.

Yu Q, Shen W, Zhou H, et al.
Knockdown of LI-cadherin alters expression of matrix metalloproteinase-2 and -9 and galectin-3.
Mol Med Rep. 2016; 13(5):4469-74 [PubMed] Related Publications
Liver-intestine cadherin (LI-cadherin), a novel member of the cadherin family, has been associated with the ability of a tumor to acquire an aggressive phenotype in several types of cancer. However, the exact function of LI-cadherin in the process of tumor invasion and metastasis remains predominantly unknown. To explore the effect of LI-cadherin on the regulation of matrix metalloproteinase-2 (MMP-2), MMP-9 and galectin-3 in LoVo human colorectal cancer cells, a RNA interference technique was applied to suppress the expression of LI‑cadherin. Subsequently, the mRNA levels and activities of MMP-2 and -9 were analyzed by semi-quantitative reverse transcription-polymerase chain reaction and gelatin zymography, respectively. Additionally, the protein expression level of galectin-3 was determined by western blot analysis. The results of the present study demonstrated that short hairpin RNA (shRNA)-silencing of LI-cadherin significantly increased the mRNA levels and activities of MMP‑2 and ‑9, and significantly reduced the protein levels of galectin‑3 in LoVo cells compared with control shRNA (P<0.05). These data indicate that knockdown of LI‑cadherin facilitates the invasion of cancer cells by degrading extracellular matrix components via activation of MMP‑2 and ‑9, and increases cancer cell adhesion and migration via altered expression of galectin‑3. This suggests that LI‑cadherin serves an important role in the invasion and metastasis of colorectal cancer, and may be used as a potential therapeutic target.

Kato I, Iribe Y, Nagashima Y, et al.
Fluorescent and chromogenic in situ hybridization of CEN17q as a potent useful diagnostic marker for Birt-Hogg-Dubé syndrome-associated chromophobe renal cell carcinomas.
Hum Pathol. 2016; 52:74-82 [PubMed] Related Publications
Birt-Hogg-Dubé syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82, and Ksp-cadherin similar to their sporadic counterparts. Highly reliable markers for BHD-associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs, and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm. All chromophobe RCCs and HOCTs were disomic except for 1 chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic (P = .0008). The state of chromosomes 2 and 6 were also statistically different (P = .0074 and P = .0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that fluorescent and chromogenic in situ hybridization of the centromeric region of chromosome 17 long arm should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing.

Li WB, Zhou J, Xu L, et al.
Identification of Genes Associated with Papillary Thyroid Carcinoma (PTC) for Diagnosis by Integrated Analysis.
Horm Metab Res. 2016; 48(4):226-31 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, and our understanding of its pathogenesis is incomplete. To elucidate the mechanisms underlying such progression and identify novel diagnostic markers, we aimed to discover the underlying gene associated with PTC. Integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between PTCs and normal tissues. GO enrichment analysis and KEGG pathway enrichment analysis were then performed to uncover the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. Five GEO datasets were obtained. Totally, 154 DEGs across the studies were identified, including 26 upregulated and 128 downregulated DEGs. In the PPI network, MLLT1, DLG2, and EFEMP1 were the hub proteins, in which DLG2 and EFEMP1 were involved in tumor progression. Among the top 10 up- and downregulated genes, the dysregulation genes of TPO, CDH16, and MPPED2 may be closely related to the tumorigenesis of PTC. By integrated analysis of multiple gene expression profiles, we propose that the dysregulation genes of TPO and MPPED2 will be the promising diagnostic markers for PTCs.

Kim YI, Lee J, Choi YJ, et al.
Proteogenomic Study beyond Chromosome 9: New Insight into Expressed Variant Proteome and Transcriptome in Human Lung Adenocarcinoma Tissues.
J Proteome Res. 2015; 14(12):5007-16 [PubMed] Related Publications
This is a report of a human proteome project (HPP) related to chromosome 9 (Chr 9). To reveal missing proteins and undiscovered features in proteogenomes, both LC-MS/MS analysis and next-generation RNA sequencing (RNA-seq)-based identification and characterization were conducted on five pairs of lung adenocarcinoma tumors and adjacent nontumor tissues. Before our previous Chromosome-Centric Human Proteome Project (C-HPP) special issue, there were 170 remaining missing proteins on Chr 9 (neXtProt 2013.09.26 rel.); 133 remain at present (neXtProt 2015.04.28 rel.). In the proteomics study, we found two missing protein candidates that require follow-up work and one unrevealed protein across all chromosomes. RNA-seq analysis detected RNA expression for four nonsynonymous (NS) single nucleotide polymorphisms (SNPs) (in CDH17, HIST1H1T, SAPCD2, and ZNF695) and three synonymous SNPs (in CDH17, CST1, and HNF1A) in all five tumor tissues but not in any of the adjacent normal tissues. By constructing a cancer patient sample-specific protein database based on individual RNA-seq data and by searching the proteomics data from the same sample, we identified four missense mutations in four genes (LTF, HDLBP, TF, and HBD). Two of these mutations were found in tumor samples but not in paired normal tissues. In summary, our proteogenomic study of human primary lung tumor tissues detected additional and revealed novel missense mutations and synonymous SNP signatures, some of which are specific to lung cancers. Data from mass spectrometry have been deposited in the ProteomeXchange with the identifier PXD002523.

Sethi MK, Thaysen-Andersen M, Kim H, et al.
Quantitative proteomic analysis of paired colorectal cancer and non-tumorigenic tissues reveals signature proteins and perturbed pathways involved in CRC progression and metastasis.
J Proteomics. 2015; 126:54-67 [PubMed] Related Publications
Modern proteomics has proven instrumental in our understanding of the molecular deregulations associated with the development and progression of cancer. Herein, we profile membrane-enriched proteome of tumor and adjacent normal tissues from eight CRC patients using label-free nanoLC-MS/MS-based quantitative proteomics and advanced pathway analysis. Of the 948 identified proteins, 184 proteins were differentially expressed (P<0.05, fold change>1.5) between the tumor and non-tumor tissue (69 up-regulated and 115 down-regulated in tumor tissues). The CRC tumor and non-tumor tissues clustered tightly in separate groups using hierarchical cluster analysis of the differentially expressed proteins, indicating a strong CRC-association of this proteome subset. Specifically, cancer associated proteins such as FN1, TNC, DEFA1, ITGB2, MLEC, CDH17, EZR and pathways including actin cytoskeleton and RhoGDI signaling were deregulated. Stage-specific proteome signatures were identified including up-regulated ribosomal proteins and down-regulated annexin proteins in early stage CRC. Finally, EGFR(+) CRC tissues showed an EGFR-dependent down-regulation of cell adhesion molecules, relative to EGFR(-) tissues. Taken together, this study provides a detailed map of the altered proteome and associated protein pathways in CRC, which enhances our mechanistic understanding of CRC biology and opens avenues for a knowledge-driven search for candidate CRC protein markers.

Oue N, Sentani K, Sakamoto N, Yasui W
Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype.
Cancer Sci. 2015; 106(8):951-8 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Gastric cancer (GC), one of the most common human cancers, can be classified into gastric or intestinal phenotype according to mucin expression. TP53 mutation, allelic deletion of the APC gene and nuclear staining of β-catenin are frequently detected in the intestinal phenotype of GC, whereas CDH1 gene mutation, microsatellite instability and DNA hypermethylation of MLH1 are common events in the gastric phenotype of GC. Our Serial Analysis of Gene Expression (SAGE) and Escherichia coli ampicillin secretion trap (CAST) analyses revealed that CDH17, REG4, OLFM4, HOXA10, DSC2, TSPAN8 and TM9SF3 are upregulated in GC and that CLDN18 is downregulated in GC. Expression of CDH17, REG4, HOXA10 and DSC2 and downregulation of CLDN18 are observed in the intestinal phenotype of GC. In contrast, OLFM4 is expressed in the gastric phenotype of GC. Expression of TSPAN8, TM9SF3 and HER2 are not associated with either gastric or intestinal phenotypes. Ectopic CDX2 expression plays a key function in the GC intestinal phenotype. MUC2, CDH17, REG4, DSC2 and ABCB1 are direct targets of CDX2. Importantly, these genes encode transmembrane/secretory proteins, indicating that the microenvironment as well as cancer cells are also different between gastric and intestinal phenotypes of GC.

Cutcutache I, Suzuki Y, Tan IB, et al.
Exome-wide Sequencing Shows Low Mutation Rates and Identifies Novel Mutated Genes in Seminomas.
Eur Urol. 2015; 68(1):77-83 [PubMed] Related Publications
BACKGROUND: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors.
OBJECTIVE: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations.
DESIGN, SETTING, AND PARTICIPANTS: Eight seminomas and matched normal samples were surgically obtained from eight patients.
INTERVENTION: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality.
RESULTS AND LIMITATIONS: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic.
CONCLUSIONS: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy.
PATIENT SUMMARY: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.

Wang F, Lin F, Zhang P, et al.
Thioredoxin-1 inhibitor, 1-methylpropyl 2-imidazolyl disulfide, inhibits the growth, migration and invasion of colorectal cancer cell lines.
Oncol Rep. 2015; 33(2):967-73 [PubMed] Related Publications
1-Methylpropyl 2-imidazolyl disulfide (PX-12) has been proposed as an inhibitor of thioredoxin-1 (Trx-1) with antitumor activity. However, the antitumor activity of the Trx-1 redox signaling inhibitor PX-12 on colorectal cancer is still obscure. In the present study, we showed that PX-12 inhibited the growth of colorectal cancer DLD-1 and SW620 cells in a dose- and time-dependent manner. Further analysis demonstrated that PX-12 reduced cell colony formation and induced a G2/M phase arrest of the cell cycle. In addition, PX-12 treatment induced apoptosis, as observed by the increased number of Annexin V-positive cells and increased activation of caspase-3. Notably, a low dose of PX-12 inhibited colorectal cancer cell migration and invasion. Treatment of cancer cells with PX-12 reduced NOX1, CDH17 and S100A4 mRNA expression, and increased KLF17 mRNA expression. Moreover, PX-12 decreased S100A4 protein expression in the colorectal cancer cells. Collectively, the present study demonstrates the antitumor effects and therapeutic potential of PX-12 in colorectal cancer.

di Martino E, Kelly G, Roulson JA, Knowles MA
Alteration of cell-cell and cell-matrix adhesion in urothelial cells: an oncogenic mechanism for mutant FGFR3.
Mol Cancer Res. 2015; 13(1):138-48 [PubMed] Related Publications
UNLABELLED: Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell-cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell-cell adhesion, with large intercellular spaces observable at confluence, and diminished cell-substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell-cell and cell-matrix adhesive properties of urothelial cells.
IMPLICATIONS: The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions.

Qiu HB, Zhang LY, Ren C, et al.
Targeting CDH17 suppresses tumor progression in gastric cancer by downregulating Wnt/β-catenin signaling.
PLoS One. 2013; 8(3):e56959 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
PURPOSE: Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease.
METHODS: Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting.
RESULTS: CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/β-catenin signaling.
CONCLUSION: Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.

Lin ME, Huang D, Deng BH, et al.
Expression and functional role of Cdx2 in intestinal metaplasia of cystitis glandularis.
J Urol. 2013; 190(3):1083-9 [PubMed] Related Publications
PURPOSE: Cdx2 is an essential transcription factor in intestinal epithelial cell differentiation and proliferation. However, to our knowledge the expression and role of Cdx2 in the development of intestinal cystitis glandularis, a metaplastic lesion induced by chronic inflammation, remained to be explored.
MATERIALS AND METHODS: Real-time polymerase chain reaction was used to examine Cdx2, LI-cadherin and villin expression in typical and intestinal cystitis glandularis, and normal bladder tissue. Cdx2 cDNA was subcloned to the retroviral vector pLNCX2 for subsequent transfection into human bladder urothelium cells and rat bladder urothelium. Cdx2 mRNA and protein levels, and cell morphology and proliferation were assessed after transfection using real-time polymerase chain reaction, phase contrast microscopy, transmission electron microscopy and MTT assay, respectively.
RESULTS: Higher mRNA levels of Cdx2, villin and LI-cadherin were detected in intestinal cystitis glandularis compared to normal bladder and typical cystitis glandularis. Only Cdx2 groups attained statistical significance (p <0.001). Retroviral over expression of Cdx2 resulted in increased mRNA and protein expression of Cdx2 as well as villin and LI-cadherin levels, and increased cell proliferation. A distinct change in cellular morphology, in which cells resembled intestinal-like cells, was also observed in vitro and in vivo.
CONCLUSIONS: Cdx2 may have a critical role in regulating intestinal metaplasia in cystitis glandularis. Further studies are planned to assess the potential of using Cdx2 as a marker and therapeutic target for cystitis glandularis.

Rana S, Malinowska K, Zöller M
Exosomal tumor microRNA modulates premetastatic organ cells.
Neoplasia. 2013; 15(3):281-95 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Tumor exosomes educate selected host tissues toward a prometastatic phenotype. We demonstrated this for exosomes of the metastatic rat adenocarcinoma BSp73ASML (ASML), which modulate draining lymph nodes and lung tissue to support settlement of poorly metastatic BSp73ASML-CD44v4-v7 knockdown (ASML-CD44v(kd)) cells. Now, we profiled mRNA and microRNA (miRNA) of ASML(wt) and ASML-CD44v(kd) exosomes to define the pathway(s), whereby exosomes prepare the premetastatic niche. ASML exosomes, recovered in draining lymph nodes after subcutaneous injection, preferentially are taken up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. ASML(wt) and ASML-CD44v(kd) exosomes contain a restricted mRNA and miRNA repertoire that differs significantly between the two lines and exosomes thereof due to CD44v6 influencing gene and miRNA transcription/posttranscriptional regulation. Exosomal mRNA and miRNA are recovered in target cells, where transferred miRNA significantly affected mRNA translation. Besides others, this was exemplified for abundant ASML(wt)-exosomal miR-494 and miR-542-3p, which target cadherin-17 (cdh17). Concomitantly, matrix metalloproteinase transcription, accompanying cdh17 down-regulation, was upregulated in LnStr transfected with miR-494 or miR-542-3p or co-cultured with tumor exosomes. Thus, tumor exosomes target non-transformed cells in premetastatic organs and modulate premetastatic organ cells predominantly through transferred miRNA, where miRNA from a metastasizing tumor prepares premetastatic organ stroma cells for tumor cell hosting. Fitting the demands of metastasizing tumor cells, transferred exosomal miRNA mostly affected proteases, adhesion molecules, chemokine ligands, cell cycle- and angiogenesis-promoting genes, and genes engaged in oxidative stress response. The demonstration of function-competent exosomal miRNA in host target cells encourages exploiting exosomes as a therapeutic gene delivery system.

Chen RY, Cao JJ, Chen J, et al.
Single nucleotide polymorphisms in the CDH17 gene of colorectal carcinoma.
World J Gastroenterol. 2012; 18(48):7251-61 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
AIM: To investigate the relationship between c.343A>G and c.2216A>C polymorphism sites in the CDH17 gene and colorectal carcinoma.
METHODS: Ninety-three non-consanguineous colorectal carcinoma patients admitted to the Department of Oncology at the First Affiliated Hospital of Zhengzhou University were included in this study. Ninety-three peripheral venous blood samples, of approximately one milliliter from each patient, were collected between December 2009 and August 2010. The genomic DNA of these peripheral venous blood samples were extracted and purified using a Fermentas Genomic DNA Purification Kit (Fermentas, CA) according to the manufacturer's protocol. The single nucleotide polymorphisms (SNPs) of the liver-intestine cadherin (CDH17) gene c.343A>G and c.2216A>C were determined by the polymerase chain reaction-single strand conformation polymorphism method (PCR-SSCP) in 93 peripheral venous blood samples from patients suffering with colorectal carcinoma. Typical samples that showed different migration bands in SSCP were confirmed by sequencing. Directed DNA sequencing was used to check the correctness of the genotype results from the PCR-SSCP method.
RESULTS: There was a significant association between the c.2216 A>C SNPs of the CDH17 gene and the tumor-node-metastasis (TNM) grade, as well as with lymph node status, in 93 peripheral venous blood samples from colorectal carcinoma patients. The genotype frequencies of A/C, A/A, and C/C were 12.90%, 33.33% and 53.76%, respectively. There was a significant correlation between lymph node metastasis, TNM grade, and the genotype distribution (P < 0.05). The C/C genotype raised the risk of lymph node metastasis and the TNM grade. There was a significant difference in the TNM grade and lymph node metastasis between the A/A and C/C genotypes (P = 0.003 and P = 0.013, respectively). Patients with colorectal carcinoma carrying the C allele tended to have a higher risk of lymph node metastasis and have a higher TNM grade. The difference between the TNM grades, as well as the lymph node metastasis of the two alleles, was statistically significant (P < 0.01).
CONCLUSION: The SNPs of the CDH17 gene c.2216 A>C might be clinically important in the prognosis of colorectal carcinoma.

Takamura M, Yamagiwa S, Matsuda Y, et al.
Involvement of liver-intestine cadherin in cancer progression.
Med Mol Morphol. 2013; 46(1):1-7 [PubMed] Related Publications
Cadherins constitute a superfamily of Ca(2+)-dependent cell adhesion molecules that play critical roles in the maintenance of tissue structure and morphogenesis. Their dysregulation is commonly observed in a variety of cancers. Liver-intestine cadherin (LI-cadherin), which was so named in view of its sole expression in the liver and intestine of the rat, is a structurally unique member of the cadherin superfamily, possessing seven cadherin repeats within the extracellular cadherin domain and only 25 amino acids in the cytoplasmic domain. Its adhesive property does not require any interaction with cytoplasmic components such as catenins, and it responds to small changes in extracellular Ca(2+) below the physiological plasma concentration. In humans, the distribution of LI-cadherin is limited to the duodenum, jejunum, ileum, colon, and part of the pancreatic duct. Data accumulated from studies of the biological characteristics of LI-cadherin have shown that it plays an important role in the pathophysiology of human cancers. Here, we review recent information about LI-cadherin and its implications for cancer progression.

Hasumi H, Baba M, Hasumi Y, et al.
Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN.
J Natl Cancer Inst. 2012; 104(22):1750-64 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood.
METHODS: Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided.
RESULTS: Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney.
CONCLUSION: FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.

Mokrowiecka A, Zonnur S, Veits L, et al.
Liver-intestine-cadherin is a sensitive marker of intestinal differentiation during Barrett's carcinogenesis.
Dig Dis Sci. 2013; 58(3):699-705 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
BACKGROUND: Histopathologic differentiation between the stages of Barrett's carcinogenesis is often challenging. Liver-intestine (LI)-cadherin, an intestine-specific marker, is involved in intestinal metaplasia development in gastric and colon cancers and could be of value in diagnosis and differentiation.
AIMS: To examine the expression of LI-cadherin in the sequence of Barrett's carcinogenesis and to evaluate its association with clinicopathological data.
METHODS: LI-cadherin expression was immunohistologically investigated, by use of anti-CDH17 antibody, in gastric mucosa (GM) biopsies taken from the cardia (n = 9), in Barrett's esophagus (BE) without intraepithelial neoplasia (without IEN) (n = 9) and BE with low-grade IEN (n = 11), and in esophageal adenocarcinoma (ADC) (n = 13).
RESULTS: The immunoreactivity score was highest in adenocarcinoma (mean IRS = 4.0), and dropped gradually from BE with IEN and BE without IEN (mean IRS = 2.0) to cardia mucosa (IRS = 0). Similarly, the intensity of staining and the percentage of positive cells increased during the sequential stages of BE carcinogenesis. Comparative analysis showed that LI-cadherin expression was significantly different between cardiac epithelium and ADC. Also, percentage of positive cells in GM was significantly different from that in BE with IEN. LI-cadherin IRS was lower for tumors with poor differentiation than for moderately differentiated tumors, but the difference was not statistically significant.
CONCLUSIONS: LI-cadherin is a sensitive marker of intestinal metaplasia and can be helpful for early histologic diagnosis of Barrett's esophagus; it is, however, not significantly different between BE with and without IEN, and cannot be used to distinguish between these.

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