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• W2146867769 abstract "P-cadherin belongs to the family of classic cadherins, which is important for maintaining cellular localization and tissue integrity. Recently, it has become evident that P-cadherin contributes to the oncogenesis of many tumor types, including melanoma, prostate, breast, and colon carcinomas. Although cadherin switching is a crucial step in metastasis, the role of P-cadherin in colon cancer metastasis to the liver is unknown. In this study, we performed gene expression analysis and found that the level of P-cadherin was higher in tissue from liver metastases of colon cancer than in the corresponding primary colon cancer tissues. IHC analysis also showed that P-cadherin expression was significantly higher in liver metastases than in paired primary colorectal cancer tumors. Knockdown of P-cadherin in colon cancer cells inhibited wound healing, proliferation, and colony formation and resulted in developing fewer liver metastatic foci and reducing the tumor burden in vivo. Inhibition of P-cadherin expression also induced the up-regulation of E-cadherin and the down-regulation of β-catenin and its downstream target molecules, including survivin and c-Myc. In summary, these results uncover a novel function of P-cadherin in the regulation of colon cancer metastasis to the liver, suggesting that blocking the activity of P-cadherin or its associated signaling may be a valuable target for the treatment of hepatic metastases of colon carcinomas. P-cadherin belongs to the family of classic cadherins, which is important for maintaining cellular localization and tissue integrity. Recently, it has become evident that P-cadherin contributes to the oncogenesis of many tumor types, including melanoma, prostate, breast, and colon carcinomas. Although cadherin switching is a crucial step in metastasis, the role of P-cadherin in colon cancer metastasis to the liver is unknown. In this study, we performed gene expression analysis and found that the level of P-cadherin was higher in tissue from liver metastases of colon cancer than in the corresponding primary colon cancer tissues. IHC analysis also showed that P-cadherin expression was significantly higher in liver metastases than in paired primary colorectal cancer tumors. Knockdown of P-cadherin in colon cancer cells inhibited wound healing, proliferation, and colony formation and resulted in developing fewer liver metastatic foci and reducing the tumor burden in vivo. Inhibition of P-cadherin expression also induced the up-regulation of E-cadherin and the down-regulation of β-catenin and its downstream target molecules, including survivin and c-Myc. In summary, these results uncover a novel function of P-cadherin in the regulation of colon cancer metastasis to the liver, suggesting that blocking the activity of P-cadherin or its associated signaling may be a valuable target for the treatment of hepatic metastases of colon carcinomas. Colon cancer is one of the most common cancers in the world and has a high propensity for liver metastasis.1Wicherts D.A. de Haas R.J. Borel Rinkes I.H. Voest E.E. van Hillegersberg R. Better treatment for patients with colorectal liver metastases.Ned Tijdschr Geneeskd. 2006; 150: 345-351PubMed Google Scholar, 2Ochiai H. Nakanishi Y. Fukasawa Y. Sato Y. Yoshimura K. Moriya Y. Kanai Y. Watanabe M. Hasegawa H. Kitagawa Y. Kitajima M. Hirohashi S. A new formula for predicting liver metastasis in patients with colorectal cancer: immunohistochemical analysis of a large series of 439 surgically resected cases.Oncology. 2008; 75: 32-41Crossref PubMed Scopus (18) Google Scholar The primary cause of death in patients with colon cancer is liver metastasis,3Bakalakos E.A. Kim J.A. Young D.C. Martin Jr, E.W. Determinants of survival following hepatic resection for metastatic colorectal cancer.World J Surg. 1998; 22: 399-404Crossref PubMed Scopus (132) Google Scholar and 5-year overall survival is only 25% to 40%.3Bakalakos E.A. Kim J.A. Young D.C. Martin Jr, E.W. Determinants of survival following hepatic resection for metastatic colorectal cancer.World J Surg. 1998; 22: 399-404Crossref PubMed Scopus (132) Google Scholar, 4Choti M.A. Sitzmann J.V. Tiburi M.F. Sumetchotimetha W. Rangsin R. Schulick R.D. Lillemoe K.D. Yeo C.J. Cameron J.L. Trends in long-term survival following liver resection for hepatic colorectal metastases.Ann Surg. 2002; 235: 759-766Crossref PubMed Scopus (1242) Google Scholar Early treatment targeting colon cancer liver metastatic foci might be important for improving patient survival. Therefore, there is an urgent need to identify molecules that facilitate the metastasis of colon cancer to the liver, which would be potential therapeutic targets for treating patients with colon cancer and liver metastases. Cancer metastasis is a complex process involving many genes that function in the tumor cell and at the target organ.5Bos P.D. Zhang X.H.F. Nadal C. Shu W. Gomis R.R. Nguyen D.X. Minn A.J. van de Vijver M.J. Gerald W.L. Foekens J.A. Massague J. Genes that mediate breast cancer metastasis to the brain.Nature. 2009; 459: 1005-1009Crossref PubMed Scopus (1291) Google Scholar, 6Minn A.J. Gupta G.P. Siegel P.M. Bos P.D. Shu W. Giri D.D. Viale A. Olshen A.B. Gerald W.L. Massague J. Genes that mediate breast cancer metastasis to lung.Nature. 2005; 436: 518-524Crossref PubMed Scopus (2269) Google Scholar In the past, gene array technology has been used to identify different genes relevant to cancer metastasis.7Smith S.C. Nicholson B. Nitz M. Frierson Jr, H.F. Smolkin M. Hampton G. El-Rifai W. Theodorescu D. Profiling bladder cancer organ site-specific metastasis identifies LAMC2 as a novel biomarker of hematogenous dissemination.Am J Pathol. 2009; 174: 371-379Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar P-cadherin, one of the classic cadherins, has an extracellular N-terminal domain, a transmembrane domain, and a cytoplasmic carboxy-terminal domain. The cytoplasmic domain of the classic cadherins binds the catenin family members.8Ben-Ze'ev A. Geiger B. Differential molecular interactions of β-catenin and plakoglobin in adhesion, signaling and cancer.Curr Opin Cell Biol. 1998; 10: 629-639Crossref PubMed Scopus (306) Google Scholar The cadherin-catenin interactions are necessary to maintain the cell-cell adhesion function of the cadherin complex.9Drees F. Pokutta S. Yamada S. Nelson W.J. Weis W.I. α-Catenin is a molecular switch that binds E-cadherin-β-catenin and regulates actin-filament assembly.Cell. 2005; 123: 903-915Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar, 10Jankowski J.A. Bruton R. Shepherd N. Sanders D.S. Cadherin and catenin biology represent a global mechanism for epithelial cancer progression.Mol Pathol. 1997; 50: 289-290Crossref PubMed Scopus (71) Google Scholar Accumulating evidence shows that perturbation of P-cadherins is strongly associated with carcinogenesis and confers malignant phenotype on cancer cells.11Hibi K. Goto T. Mizukami H. Kitamura Y.H. Sakuraba K. Sakata M. Saito M. Ishibashi K. Kigawa G. Nemoto H. Sanada Y. Demethylation of the CDH3 gene is frequently detected in advanced colorectal cancer.Anticancer Res. 2009; 29: 2215-2217PubMed Google Scholar, 12Hibi K. Kitamura Y.H. Mizukami H. Goto T. Sakuraba K. Sakata M. Saito M. Ishibashi K. Kigawa G. Nemoto H. Sanada Y. Frequent CDH3 demethylation in advanced gastric carcinoma.Anticancer Res. 2009; 29: 3945-3947PubMed Google Scholar, 13Paredes J. Albergaria A. Oliveira J.T. Jeronimo C. Milanezi F. Schmitt F.C. P-cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation.Clin Cancer Res. 2005; 11: 5869-5877Crossref PubMed Scopus (202) Google Scholar For example, overexpression of P-cadherin is likely to be related to the biologic aggressiveness in pancreatic carcinoma.14Taniuchi K. Nakagawa H. Hosokawa M. Nakamura T. Eguchi H. Ohigashi H. Ishikawa O. Katagiri T. Nakamura Y. Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases.Cancer Res. 2005; 65: 3092-3099PubMed Google Scholar Similarly, up-regulation of P-cadherin could promote bladder carcinoma cell migration and be associated with a poor clinical outcome and prognosis.15Mandeville J.A. Silva Neto B. Vanni A.J. Smith G.L. Rieger-Christ K.M. Zeheb R. Loda M. Libertino J.A. Summerhayes I.C. P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells.BJU Int. 2008; 102: 1707-1714Crossref PubMed Scopus (35) Google Scholar Although P-cadherin contributing to colon cancer progression has been reported,2Ochiai H. Nakanishi Y. Fukasawa Y. Sato Y. Yoshimura K. Moriya Y. Kanai Y. Watanabe M. Hasegawa H. Kitagawa Y. Kitajima M. Hirohashi S. A new formula for predicting liver metastasis in patients with colorectal cancer: immunohistochemical analysis of a large series of 439 surgically resected cases.Oncology. 2008; 75: 32-41Crossref PubMed Scopus (18) Google Scholar the role of P-cadherin in the metastasis of colon cancer to liver has not been explored. In this study, we performed cDNA microarray and IHC analysis and identified that P-cadherin was significantly associated with liver metastasis. Then, we investigated the role of P-cadherin in colon cancer liver metastasis in vivo and in vitro. These results, for the first time, imply that P-cadherin plays a key role in colon cancer hepatic metastasis. The colon cancer cell lines LoVo, Colo205, and Ls174T were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 100 U/mL of penicillin/streptomycin (all from Invitrogen, Carlsbad, Ca). The colon cancer cell lines Colo320DM, SW480, SW620, Ls180, SW1116, HT29, and Hct1116 were maintained in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with 10% fetal bovine serum and 100 U/mL of penicillin/streptomycin (Invitrogen). Anti–P-cadherin antibodies were purchased from BD Biosciences (Franklin Lakes, NJ). Anti–β-catenin, anti-survivin, anti-cyclin D1, and anti–E-cadherin antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-vimentin, anti-snail, anti-slug, anti–c-Myc, anti–c-Jun, and anti–N-cadherin antibodies were purchased from Cell Signaling Technology Inc. (Beverly, MA). Anti–p120-catenin antibodies were purchased from Epitomics Inc. (Burlingame, CA). Horseradish peroxidase–conjugated anti-rabbit and anti-mouse antibodies were obtained from Jackson ImmunoResearch Laboratories Inc. (West Grove, PA). Anti–β-actin monoclonal antibodies were purchased from Sigma-Aldrich Corp. (St. Louis, MO). Lipofectamine 2000 was obtained from Invitrogen. Two small-interfering RNAs based on the P-cadherin sequences (5′-GGAGACAGGCTGGTTGTTG-3′ and 5′-CAUAUGACGUGCACCUUUC-3′) were synthesized by RiboBio Inc. (Guangzhou, China). For stable knockdown of P-cadherin, the oligoduplexes were cloned into psiTarget 2.0-CMV-RFP-Neo siRNA vector (GeneChem, Shanghai, China) and were transfected into cells using Lipofectamine 2000 (Invitrogen). Transfected cells were selected by 500 μg/mL of G418 for 2 weeks. Resistant clones were picked for expansion and characterization. P-cadherin expression was determined by Western blot and RT-PCR. Cells stably expressing short hairpin P-cadherin were designated as P-cadherin short hairpin RNA (shRNA) cells. Negative control cell lines were generated by infecting cells with a psiTarget 2.0-CMV-RFP-Neo vector construct targeting enhanced red fluorescent protein cDNA. The microarray experimental procedures were described previously.16Hu H. Sun L. Guo C. Liu Q. Zhou Z. Peng L. Pan J. Yu L. Lou J. Yang Z. Zhao P. Ran Y. Tumor cell-microenvironment interaction models coupled with clinical validation reveal CCL2 and SNCG as two predictors of colorectal cancer hepatic metastasis.Clin Cancer Res. 2009; 15: 5485-5493Crossref PubMed Scopus (72) Google Scholar, 17Patterson T.A. Lobenhofer E.K. Fulmer-Smentek S.B. Collins P.J. Chu T.-M. Bao W. Fang H. Kawasaki E.S. Hager J. Tikhonova I.R. Walker S.J. Zhang L. Hurban P. de Longueville F. Fuscoe J.C. Tong W. Shi L. Wolfinger R.D. Performance comparison of one-color and two-color platforms within the Microarray Quality Control (MAQC) project.Nat Biotech. 2006; 24: 1140-1150Crossref PubMed Scopus (406) Google Scholar The Human Genome Oligonucleotide Set (Version 2.1), consisting of 5′-amino acid–modified 70-mer probes and representing 21,329 well-characterized Homo sapiens genes, was purchased from QIAGEN GmbH (Hilden, Germany) and was printed on aminosilane-coated glass slides. Total RNA from primary colon cancer and liver metastasis samples was prepared for probing and then was hybridized using a human genomic 70-mer oligonucleotide microarray obtained from CapitalBio Corp. (Beijing, China). Five micrograms of DNase-treated total RNA was prepared, and fluorescent dye (Cy5 and Cy3-dCTP)–labeled cDNA was produced using Eberwine's linear RNA amplification method and subsequent enzymatic reaction. The cDNAs were then hybridized to an array. Arrays were scanned using a confocal LuxScan scanner, and the images obtained were analyzed using LuxScan 3.0 software (CapitalBio Corp.). Then, space- and intensity-dependent normalization based on LOWESS in the R language package (http://www.R-project.org, last accessed November 28, 2009) was used to normalize the two-channel ratio value. Candidate genes for liver metastasis were first extracted using a specified algorithm: significance analysis of microarrays (http://www-stat.stanford.edu/∼tibs/SAM, last accessed December 3, 2009), which can statistically extract and quantify differences in gene expression between two groups. For this study, a fold change >1.5 and q < 0.05 were used to identify genes that may promote liver metastasis. The tissues samples were from the Cancer Institute (Hospital), Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China). All the studies were preapproved by the Institutional Review Board, and informed consent forms were signed by all the study participants. We enrolled patients with colon cancer with or without liver metastasis, and patients with colon cancer and other organ involvement were not included in this study. Colorectal cancer cases with no history of liver metastasis were designated M0 (96 cases); those with a history of liver metastasis were designated M1 (106 cases). TMAs were prepared from archival formalin-fixed, paraffin-embedded tissue blocks. For each tumor, a representative tumor area was carefully selected from an H&E-stained section. A total of 202 specimens were placed on the TMA. For each case, normal tissues were repeated twice and cancer tissues were repeated five times. Clinical follow-up records are available for all the samples. In addition, we collected 30 colon cancer specimens with paired liver metastases for testing the expression of P-cadherin by immunohistochemical (IHC) analysis and RT-PCR. The avidin-biotin complex method was used for IHC analysis. Briefly, after deparaffinization in xylene and graded alcohols, heated antigen retrieval was performed in citrate buffer (10 mmol/L, pH 6.0) by water bath kettle heating for 30 minutes. Next, endogenous peroxidase activity was blocked by incubating samples in 0.3% hydrogen peroxide for 10 minutes. Then, nonspecific binding was blocked by incubating samples in 10% normal animal serum for 10 minutes. Next, sections were incubated with primary antibodies against P-cadherin (610228, BD Biosciences), 1:50; E-cadherin (sc-7870, Santa Cruz Biotechnology), 1:200; and β-catenin (sc-7963, Santa Cruz Biotechnology), 1:100, at 4°C for 24 hours. Next, biotinylated secondary antibodies and horseradish peroxidase–labeled avidin were incubated with samples. Color was developed using the diaminobenzidine method. Expression analysis of proteins in malignant and epithelial cells was performed by comparing staining intensity and the percentage of immunoreactive cells. Staining intensity was arbitrarily scored on a scale of four grades: 0 (no staining of cancer cells), 1 (weak staining), 2 (moderate staining), and 3 (strong staining), and the percentage of positive cells was scored as follows: 0 (0%), 1 (1% to 25%), 2 (26% to 50%), and 3 (>50%). P-cadherin and E-cadherin staining positivity was determined using the following formula: overall score = positive percentage score × intensity score. A score of 0 was defined as “0,” >0 to ≤2 as “1,” >2 to ≤6 as “2,” and >6 to ≤9 as “3.” In the end, colon cancer samples rated as level 0 or 1 were defined as negative for expression, whereas samples rated as level 2 or 3 were defined as positive. For the evaluation of β-catenin immunoreactivity, nuclear staining of malignant cells was regarded as positive, regardless of cytoplasmic staining. Immunostained sections were classified into two groups based on the proportion of positively stained tumor cells that had positive nuclear staining in the lesion: 0 (negative or positive but in ≤10% of tumor cells) versus 1 (positive in >10% of tumor cells). Negative controls were performed by omitting the primary antibody. Blinded analysis of the slides was performed by two independent observers. For immunoblots, cellular protein lysates were prepared in radioimmunoprecipitation assay buffer, resolved on SDS-PAGE gels, and transferred to nitrocellulose membranes. The transferred proteins were visualized using enhanced chemiluminescence immunoblotting reagents (Amersham Biosciences Corp., Sunnyvale, CA). A negative control was performed to ensure the specificity of immunostaining by replacing primary antibody with a nonimmune mouse or rabbit IgG. Cells were grown to 95% confluency in a 6-well plate. A wound was created by scratching cells with a sterile 200-μL pipette tip. Cells were washed three times with serum-free medium to remove the floating cells, and fresh serum-free culturing medium was added. Photographs of the wound were taken under ×10 magnification. Cells were trypsinized and resuspended in complete medium and were seeded equally into 96-well plates. Cells were counted using Cell Counting Kit-8 (Dojindo Molecular Technologies Inc., Rockville, MD) at the indicated time points according to the manufacturer's instructions, and optical density was measured at 450 nm. These experiments were performed twice with similar results. To study anchorage-independent growth, six-well plates were layered with 1.5 mL of 0.5% agarose in Dulbecco's modified Eagle's medium with 10% fetal bovine serum and penicillin-streptomycin. Subsequently, 1000 cells mixed with 0.35% agarose were set in each well of the six-well plates to form the upper gel. After 2 weeks, pictures of colonies were taken using a digital camera after staining with 0.005% blue violet. Each treatment was performed in triplicate. Colony numbers were counted at least twice, and the data were imported into Excel spreadsheet software (Microsoft Corp., Redmond, WA) for graphing and statistical analysis. Cells were cultured for 24 hours. After rinsing with PBS, cells were fixed in PBS–4% paraformaldehyde for 30 minutes and were permeabilized with 0.1% Triton X-100 (Roche Diagnostics GmbH, Mannheim, Germany) for 10 minutes at 4°C. Cells were then incubated with P-cadherin (1:50), β-catenin (1:100), and p120-catenin (1:200) primary antibodies, followed by Cy3-conjugated anti-mouse IgG (1:200) or fluorescein isothiocyanate–conjugated anti-rabbit IgG (1:300) secondary antibodies. Samples were then mounted onto slides and were visualized using a confocal microscope (Leica Microsystems GmbH, Wetzlar, Germany). All the animal experiments were performed in full compliance with institutional guidelines and with the approval of the Animal Care and Use Committee, Cancer Institute (Hospital), Chinese Academy of Medical Sciences and Peking Union Medical College. Female nu/nu mice, obtained from The Jackson Laboratory (Vital River Laboratories, Beijing, China), were kept in a pathogen-free facility at the Experimental Center of the Chinese Academy of Medical Sciences. The facility is accredited for animal care by the Chinese Association for Accreditation of Laboratory Animal Care. For experimental liver metastases, model LoVo clones stably transfected with two shRNAs targeting distinct P-cadherin sequences or vector were harvested and resuspended in PBS at a final concentration of 2 × 107 cells/mL. Mice were anesthetized by i.p. injection of pentobarbital (60 mg/kg). Using a 10-mm left subcostal incision, the spleen was identified beneath the peritoneum and was exposed via an 8-mm peritoneal incision. A suspension of tumor cells (100 μL) was injected into the spleen using a 27-gauge needle, after which the spleen was returned to the abdominal cavity. The peritoneum was sutured with a single stitch, and the wound was closed using a clip. Mice were sacrificed 8 weeks after tumor cell inoculation. The liver with metastasis foci was used for pathologic confirmation of the liver metastasis. For tumor formation assay, LoVo P-cadherin shRNA cells, vector cells, or Ls174T P-cadherin shRNA cells were subcutaneously injected into nude mice with 1 × 106 cells per animal for each group. Forty-three days after injection, 24 mice were sacrificed, and invasive patterns were analyzed using H&E staining. The SPSS, version 15, software package (SPSS Inc., Chicago, IL) was used for statistical analysis. The two-sided t-test method was used for analysis of the number of mouse liver metastatic foci among groups. The association between the immunoreactive markers and the clinicopathologic features was analyzed using the χ2 test or the two-sided t-test, as appropriate. The survival rates were assessed by the Kaplan-Meier method and compared by the log-rank test. A P < 0.05 was considered statistically significant. To acquire genes associated with colon cancer liver metastasis, we evaluated gene expression in primary and metastatic samples using the CapitalBio Corp. human genomic 70-mer oligonucleotide microarray.18Guo Y. Guo H. Zhang L. Xie H. Zhao X. Wang F. Li Z. Wang Y. Ma S. Tao J. Wang W. Zhou Y. Yang W. Cheng J. Genomic analysis of anti-hepatitis B virus (HBV) activity by small interfering RNA and lamivudine in stable HBV-producing cells.J Virol. 2005; 79: 14392-14403Crossref PubMed Scopus (119) Google Scholar Gene array analysis revealed that there were 677 genes with significantly different expression, including 22 that were up-regulated and 655 that were down-regulated in the metastatic tissue. We focused on the genes that were up-regulated in the colon cancer liver metastatic samples (Table 1). Of the 22 up-regulated genes, 4 candidate genes, including IGFBP1,19Thakur A. Bollig A. Wu J. Liao D.J. Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice.Mol Cancer. 2008; 7: 11Crossref PubMed Scopus (32) Google Scholar HPR,20Lee C.C. Lee M.S. Ho H.C. Hung S.K. Tung Y.T. Chou P. Su Y.C. The prognostic utility of haptoglobin genotypes in squamous cell carcinoma of the head and neck.Clin Chem Lab Med. 2009; 47: 1277-1283PubMed Google Scholar CYP2E1,21Fritz P. Behrle E. Beaune P. Eichelbaum M. Kroemer H.K. Differential expression of drug metabolizing enzymes in primary and secondary liver neoplasm: immunohistochemical characterization of cytochrome P4503A and glutathione-S-transferase.Histochemistry. 1993; 99: 443-451PubMed Google Scholar and P-cadherin,22Pyo S.W. Hashimoto M. Kim Y.S. Kim C.H. Lee S.H. Johnson K.R. Wheelock M.J. Park J.U. Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: correlation with the clinicopathologic features and patient outcome.J Craniomaxillofac Surg. 2007; 35: 1-9Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar which are involved in metabolism, proliferation, and adhesion and are closely associated with cancer metastasis, were selected for further study. To confirm the microarray data, we performed semiquantitative RT-PCR and tested four candidate genes in four fresh paired primary and metastatic samples. The housekeeping gene GAPDH was used as a reference. P-cadherin was consistently up-regulated in liver metastasis samples compared with primary colon cancer samples, whereas other genes were highly expressed in a portion of the samples (Figure 1A). The results suggest that P-cadherin is associated with colon cancer liver metastasis.Table 1Genes Up-Regulated in the Liver Metastatic Tissues and Gene Ontology CategoriesGene nameRefSeqMean ratioCVScore (d)q value (%)FunctionDescriptionIGFBP1NM_00059613.190.0419.340.00ProliferationInsulin-like growth factor binding protein 1 precursorRPA3NM_0029471.770.083.663.98DNA repairReplication protein A 14 kd subunitP-cadherinNM_0017931.780.093.653.98AdhesionCadherin-3 precursorHRMT1L3NM_0057882.060.094.571.41MetabolismProtein arginine N-methyltransferase 3SCARB1NM_0055052.170.183.763.21MetabolismScavenger receptor class B member 1ADFPNM_0011222.690.244.292.03MetabolismAdipophilinCOLEC11NM_0240279.850.386.350.00MetabolismCollectin subfamily member 11 isoformTM4SF4NM_00461721.800.388.550.00ProliferationTransmembrane 4 superfamily member 4HPRNM_02099510.170.435.900.41MetabolismHaptoglobin-related protein precursorFGBNM_00514125.020.486.980.00ProliferationFibrinogen beta chain precursorSERPINA3NM_00108522.720.585.580.41MetabolismAlpha-1-antichymotrypsin precursorCRPNM_00056773.840.659.240.00Acute-phase responseC-reactive protein precursorDEFB1NM_0052187.200.653.573.98Innate immune responseBeta-defensin 1 precursorAPOBNM_00038422.070.685.460.41MetabolismApolipoprotein B-100 precursorALBNM_00047745.870.704.182.03MetabolismSerum albumin precursorAPCSNM_00163940.250.756.080.41MetabolismSerum amyloid P-component precursorFMO3NM_00100229417.570.764.760.86TransportDimethylaniline monooxygenaseAPOA1NM_00003923.950.804.481.41MetabolismApolipoprotein A-I precursorCYP2E1NM_00077315.530.833.663.98MetabolismCytochrome P450 2E1APOC3NM_00004018.500.853.793.21MetabolismApolipoprotein C-III precursorWDHD1NM_00708619.210.893.514.80TranscriptionWD repeat and HMG-box DNA binding protein 1ORM1NM_00060827.330.913.933.21Acute-phase responseAlpha-1-acid glycoprotein 2 precursorCV, coefficient variation. Open table in a new tab CV, coefficient variation. To determine whether the observed up-regulation of P-cadherin is a common feature of colon cancer liver metastasis, we evaluated the expression of P-cadherin in 30 primary colon cancer samples and paired liver metastatic samples. We found that among these 30 paired samples, P-cadherin was positive in 29 primary tumors (96.7%) and in 22 corresponding liver metastases (73.3%). The expression of P-cadherin in the hepatic metastases was noticeably higher than that in the matched primary colon cancer tissues. T-test analysis revealed that the levels of P-cadherin were significantly higher in the liver metastasis tissues than in the primary tissues (Figure 1B). To further analyze the clinical correlation of colon cancer with P-cadherin expression, we evaluated its expression in a colon carcinoma TMA containing 202 primary colon tumors. There was no detectable staining of P-cadherin in the normal epithelium, but 153 of 202 primary lesions exhibited positive staining. In addition, there were approximately 98 cases containing tumor invasion front. IHC scoring showed that 69 of 98 of the primary lesions exhibited positive staining for P-cadherin. Statistical analysis also indicated that P-cadherin expression in colon cancer was correlated only with liver metastasis (P < 0.05), and there was no significant association with other clinicopathologic variables (Table 2). The prognostic significance of P-cadherin was determined by P-cadherin staining and the corresponding clinical follow-up records. Kaplan-Meier survival analysis revealed a correlation between higher P-cadherin expression levels and shorter overall survival times (P < 0.05) (Figure 1C). Taken together, these observations indicate that overexpression of P-cadherin is significantly associated with colon cancer liver metastasis and poor prognosis in patients with colon cancer.Table 2Clinicopathologic Characteristics of the 202 Patients with Colon CancerP-cadherinP valueNegativePositiveSex, male:female (no.)31:1886:670.796Age, mean ± SD (years)57.2 ± 11.454.0 ± 14.30.384Tumor size, mean ± SD (cm)5.45 ± 4.455.34 ± 2.350.789Differentiation (no.)0.567 Well519 Moderate37120 Poor714Depth of invasion (no.)0.578 T1 + T2815 T3730 T434108Lymph node involvement (no.)0.56 N01948 N11754 N21351Liver metastasis (no.)0.027⁎P < 0.05. M03066 M11987Pearson's chi-square test was used to define statistical significance. P < 0.05. Open table in a new tab Pearson's chi-square test was used to define statistical significance. It has been reported that perturbation of cadherin expression could affect cell function23Jager T, Becker M, Eisenhardt A, Tilki D, Totsch M, Schmid KW, Romics I, Rubben H, Ergun S, Szarvas T: The prognostic value of cadherin switch in bladder cancer. Oncol Rep 23:1125–1132Google Scholar; therefore, we first evaluated the levels of P-cadherin, E-cadherin, and N-cadherin mRNA in 10 colon cancer cell lines cultured in the State Key Laboratory of Molecular Oncology. The result showed that P-cadherin mRNA levels were relatively high in 8 of 10 cell lines, excluding Colo320DM and SW620. E-cadherin mRNA levels in colon cancer cell lines were relatively low, and they were undetectable in Colo320DM, LoVo, and Ls174T. Similarly, we could not detect N-cadherin mRNA in the colon cancer cell lines except SW1116, Hct1116, Ls180, and HT29 (Figure 2A). Thus, it seems that the overexpression of P-cadherin is a prevalent phenomenon and might play a key role in colon cancer progression. 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• W2146867769 created "2016-06-24" @default.
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• W2146867769 date "2011-07-01" @default.
• W2146867769 modified "2023-09-26" @default.
• W2146867769 title "P-Cadherin Promotes Liver Metastasis and Is Associated with Poor Prognosis in Colon Cancer" @default.
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