.JPG?ad=18503&adview=true)
[Cancer Research 65, 9603-9606, November 1, 2005]
© 2005 American Association for Cancer Research
Claudin Proteins in Human Cancer: Promising New Targets for Diagnosis and Therapy
Patrice J. Morin
Laboratory of Cellular and Molecular Biology, National Institute on Aging, NIH, Baltimore, Maryland
Requests for reprints: Patrice J. Morin, Laboratory of Cellular and Molecular Biology, National Institute on Aging, NIH, Box 12, 5600 Nathan Shock Drive, Baltimore, MD 21224. Phone: 410-558-8506; Fax: 410-558-8386; E-mail: Morinp{at}grc.nia.nih.gov.
 |
Abstract
|
|---|
The tight junction proteins claudins are abnormally regulated in several human cancers. In particular, claudin-3 and claudin-4 are frequently overexpressed in several neoplasias, including ovarian, breast, pancreatic, and prostate cancers. Although the exact roles of these proteins in tumorigenesis are still being uncovered, it is clear that they represent promising targets for cancer detection, diagnosis, and therapy.
|
Claudins Are Tight Junction Proteins
|
|---|
Tight junctions, together with adherens junctions and desmosomes, form the apical junctional complex in epithelial and endothelial cellular sheets. Adherens junctions and desmosomes are responsible for the mechanical adhesion between adjacent cells, whereas tight junctions are essential for the tight sealing of the cellular sheets, thus controlling paracellular ion flux and therefore maintaining tissue homeostasis (1). Tight junctions also play a crucial role in the maintenance of cell polarity by forming a fence that prevents lateral diffusion of membrane proteins and lipids, thereby maintaining the differential composition of the apical and basolateral domains. Finally, because of the ability of tight junction proteins to recruit signaling proteins (2), tight junctions have also been hypothesized to be involved in the regulation of proliferation, differentiation, and other cellular functions.
When observed by electron microscopy, tight junctions form multiple strands that seem to provide the structural basis for adhesion between adjacent cells (1). Tight junctions are composed of three major integral membrane proteins, occludin, claudins, and junctional adhesion molecules. Although the exact roles of these proteins are not completely clear, it seems that the claudins form the backbone of the tight junction strands. The claudin family of proteins is comprised of 23 members of closely related transmembrane proteins (see Fig. 1). Although the expression pattern of claudins is tissue specific, most tissues express multiple claudins, which can interact in both homotypic and heterotypic fashion to form the tight junction strands. It is believed that the exact combination of claudin proteins within a given tissue can determine the selectivity and strength of the tight junctions. Claudins are polymerized together within a given cell and can interact with the claudin of the adjacent cells to form an adhesive structure.
View larger version (61K):
[in this window]
[in a new window]
|
Figure 1. Structure of claudins. Claudin proteins are a family of proteins containing four transmembrane domains. The extracellular loops represent promising targets for therapy using monoclonal antibodies or, in the case of claudin-3 and claudin-4, the CPE. The COOH-terminal region of claudins is phosphorylated, contains a PDZ-binding domain, and has been implicated in signal transduction.
|
|
The high degree of cellular organization typically observed in normal differentiated tissues is often lost in cancer. Tumor cells frequently exhibit abnormal tight junction function as well as decreased differentiation and cell polarity (3, 4). Loss of tight junction integrity may be particularly important in allowing the diffusion of nutrients and other factors necessary for the survival and growth of the tumor cells (5). In addition, decreased polarity and differentiation may be important for the metastatic phenotype, where individual cells must leave the primary site and enter the blood vessels to reach distant sites (6). Finally, the destruction of functional tight junctions in cancer may have a role in growth control. For example, in Drosophila, mutations in many tumor suppressor genes lead to loss of cell polarity and overproliferation of the epithelia (7). Based on the similarity between the vertebrate and Drosophila epithelia, mammalian cells are likely to require cytoarchitectural cues for cell growth control as well.
|
Claudin Expression in Cancer
|
|---|
The expression of occludin and claudins, the two major transmembrane proteins that contribute to formation of tight junctions, has been found to be altered in several cancers. An early study in the field showed that occludin was often down-regulated in gastrointestinal tumors (8). Similarly, other studies have shown that claudins are down-regulated in various cancers. For example, claudin-1 has been found to be reduced in breast cancer (9, 10) as well as in colon cancer (11). Claudin-7 has also been found down-regulated in invasive breast cancer (12) and in head and neck cancer (13). These reports of decreased tight junction protein expression in cancer are consistent with the generally accepted idea that tumorigenesis is accompanied by a disruption of tight junctions, a process that may play an important role in the loss of cohesion, invasiveness, and lack of differentiation observed in cancer cells. In addition to the down-regulation of protein levels, phosphorylation of tight junction proteins, including claudins, may affect tight junction function in cancer (14). For example, phosphorylation of claudin-1 by mitogen activated protein kinases (15) and protein kinase C (16), as well as phosphorylation of claudin-5 by cyclic AMP–dependent protein kinase (17, 18) have been reported. Also, WNK4 kinase has been shown to phosphorylate claudin-3 and claudin-4, and decrease tight junction function (19). Interestingly, phosphorylation of claudin-3 and claudin-4 in ovarian cancer cells has been shown to disrupt tight junctions (20).
Paradoxically, other studies have shown that certain claudin proteins are up-regulated in cancer. In fact, the overwhelming majority of the studies published thus far report an overexpression of claudins in various cancers (see Table 1). One of the first studies reporting this fact was a serial analysis of gene expression (SAGE) study of ovarian cancer showing that CLDN3 and CLDN4 (encoding claudin-3 and claudin-4, respectively) were among the most highly up-regulated genes in this cancer (21). Several additional reports have since confirmed the high expression of these two claudins in ovarian cancer (22–25). In addition, claudin-3 and claudin-4 have also been reported to be expressed in other cancers, such as breast (26), prostate (27), and pancreatic (28–32) cancers. Other claudins are differentially expressed in a number of human neoplasms and these data are summarized in Table 1.
|
Roles of Claudin in Cancer
|
|---|
As mentioned above, the loss of claudins and other tight junction proteins in cancer has been interpreted as a mechanism for the loss of cell adhesion and an important step in the progression of cancer to metastasis. Consistent with this hypothesis, a recent study showed that expression of claudin-4 in pancreatic cancer cells reduces invasiveness of these cells (33). In addition, claudin-1 reexpression in cancer cells can lead to increased apoptosis in three-dimensional cultures (34). On the other hand, as discussed previously, many claudins, such as claudin-3 and claudin-4, are typically up-regulated in many cancers (Table 1), suggesting that these proteins may have a positive effect on tumorigenesis. Recent work has shown that, at least in the case of ovarian cells, expression of claudin-3 and claudin-4 may lead to an increase in invasion, motility, and cell survival (35), all characteristics important for metastasis. Consistent with these in vitro findings is a report that claudin-4 expression in pancreatic intraductal papillary mucinous neoplasms was associated with a more invasive phenotype (31). Similarly, expression of claudin-3 and claudin-4 was observed in advanced ovarian cancer but not in ovarian cystadenomas (22). Therefore, the functions of claudins may be highly tissue specific and may depend on the exact molecular circuitry of the cell.
|
Claudins as Diagnosis Markers and Therapeutic Targets
|
|---|
Because of the high specificity of claudin expression patterns in cancer, it has been suggested that claudins may represent useful molecular markers for many different cancers. For example, a set of four markers, including claudin-3, was found to be sufficient to accurately identify all 158 ovarian cancers tested, including eight early-stage serous cancers (24). In addition, claudin expression may be used as a prognostic indicator because low claudin-1 expression has been shown to be associated with a poor prognosis in stage II colon cancer (11). Claudin-10 expression has also been shown to be an independent prognostic factor for hepatocellular carcinoma recurrence after curative hepatectomy (36).
Interestingly, claudin-3 and claudin-4 are receptors for the Clostridium perfringens enterotoxin (CPE; ref. 37). CPE is a single polypeptide of 35 kDa, which, upon binding to its receptors, causes cytolysis through its effects on membrane permeability. High expression of claudin-3 and claudin-4 in multiple cancers may thus represent a unique opportunity for innovative therapy using CPE (38). Prostate adenocarcinoma cells expressing claudin-3 and claudin-4 have indeed been shown to be sensitive to CPE-mediated cytolysis (27). Specificity was evident as prostate cancer cells lacking claudin-3 and claudin-4 were unaffected by CPE treatment. Similar experiments established that breast (26), ovarian (39), and pancreatic (29) cancer cells are also sensitive to CPE treatment, provided that they express claudin-3 and/or claudin-4, as these cancers often do. Interestingly, human tumors grown as xenografts in immunocompromised mice could also successfully be treated using CPE, again on the condition of claudin-3 or claudin-4 expression (26, 29, 39). Importantly, these studies showed that no significant toxicity was encountered in mice upon intratumoral CPE treatment. However, claudin-3 and/or claudin-4 are expressed in several normal human tissues, including the gut, the lungs, and the kidneys (27). This expression pattern may represent a problem in the use of CPE for systemic cancer therapy, and it remains to be seen whether this approach will be useful in the clinic. Clearly, approaches that would involve regional application of CPE would be preferable. In addition, it has been suggested that a nontoxic, but claudin-specific, COOH-terminal CPE fragment (C-CPE; ref. 40) could be delivered locally to certain normal tissues and prevent CPE toxicity. Other potential problems with the use of CPE in tumor treatment include the occasional lack of surface claudin expression (22), the possibility of an immune response against CPE in treated patients as well as the penetration of CPE into the tumor mass. Additional studies will be required to clearly ascertain these issues.
The C-CPE fragment represents another potential opportunity for the treatment of claudin-3- and claudin-4-expressing tumors. Indeed, C-CPE could be used as a specific carrier for cytotoxic agents and, therefore, provide selective drug delivery. Additionally, it has been suggested that, because C-CPE can destroy tight junctions (41), this peptide may be useful in combination therapy with conventional chemotherapeutic by increasing drug delivery to the interior of tumors. However, it seems that claudin-3 and claudin-4 expression is not necessarily associated with the formation of functional tight junctions in tumors and this approach may not be generally viable (22). Because claudins are transmembrane proteins and typically have two relatively large extracellular loops (see Fig. 1; ref. 42), these proteins may also offer promising targets for antibody-based therapy. Antibodies that specifically recognize different extracellular loops have been produced and shown to specifically bind claudins on the surface of the cell, providing a proof of principle for the approach (42).
The advent of gene expression profiling techniques has allowed the unbiased identification of genes that are differentially expressed in cancer. Although tight junction proteins have been studied for their role in tumorigenesis for many years, SAGE studies of breast (43) and ovarian (21) cancers allowed for the first time the identification of specific claudin family members as potential biomarkers for these cancers. Subsequent array analyses have confirmed these findings and also identified claudins as proteins frequently altered in cancer (see Table 1). These findings are important because the unusual expression patterns of claudins suggest utility for detection, diagnosis, and treatment of drug-resistant cancers. Although clinical trials will be required to establish this potential, basic research on claudins is likely to remain valuable for providing important insights into normal and neoplastic cellular physiology.
|
Acknowledgments
|
|---|
I thank Drs. Saraswati Sukumar, Ashani Weeraratna, Theresa D'Souza, and Rachana Agarwal for helpful comments on the manuscript.
Received 8/ 5/05.
Accepted 8/ 5/05.
|
References
|
|---|
- Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001;2:285–93.[CrossRef][Medline]
- Mitic LL, Anderson JM. Molecular architecture of tight junctions. Annu Rev Physiol 1998;60:121–42.[CrossRef][Medline]
- Weinstein RS, Merk FB, Alroy J. The structure and function of intercellular junctions in cancer. Adv Cancer Res 1976;23:23–89.[Medline]
- Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM. Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 1999;20:1425–31.[Abstract/Free Full Text]
- Mullin JM. Potential interplay between luminal growth factors and increased tight junction permeability in epithelial carcinogenesis. J Exp Zool 1997;279:484–9.[CrossRef][Medline]
- Martin TA, Jiang WG. Tight junctions and their role in cancer metastasis. Histol Histopathol 2001;16:1183–95.[Medline]
- Wodarz A. Tumor suppressors: linking cell polarity and growth control. Curr Biol 2000;10:R624–6.[CrossRef][Medline]
- Kimura Y, Shiozaki H, Hirao M, et al. Expression of occludin, tight-junction-associated protein, in human digestive tract. Am J Pathol 1997;151:45–54.[Abstract]
- Kramer F, White K, Kubbies M, Swisshelm K, Weber BH. Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer. Hum Genet 2000;107:249–56.[CrossRef][Medline]
- Tokes AM, Kulka J, Paku S, et al. Claudin-1, -3 and -4 proteins and mRNA expression in benign and malignant breast lesions: a research study. Breast Cancer Res 2005;7:R296–305.[CrossRef][Medline]
- Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE. Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Mod Pathol 2005;18:511–8.[CrossRef][Medline]
- Kominsky SL, Argani P, Korz D, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 2003;22:2021–33.[CrossRef][Medline]
- Al Moustafa AE, Alaoui-Jamali MA, Batist G, et al. Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells. Oncogene 2002;21:2634–40.[CrossRef][Medline]
- Li D, Mrsny RJ. Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin. J Cell Biol 2000;148:791–800.[Abstract/Free Full Text]
- Fujibe M, Chiba H, Kojima T, et al. Thr203 of claudin-1, a putative phosphorylation site for MAP kinase, is required to promote the barrier function of tight junctions. Exp Cell Res 2004;295:36–47.[CrossRef][Medline]
- Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White CL III, Sontag E. Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J Cell Biol 2002;158:967–78.[Abstract/Free Full Text]
- Ishizaki T, Chiba H, Kojima T, et al. Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways. Exp Cell Res 2003;290:275–88.[CrossRef][Medline]
- Soma T, Chiba H, Kato-Mori Y, et al. Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. Exp Cell Res 2004;300:202–12.[CrossRef][Medline]
- Yamauchi K, Rai T, Kobayashi K, et al. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci U S A 2004;101:4690–4.[Abstract/Free Full Text]
- D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by pka regulates tight junction barrier function in ovarian cancer cells. J Biol Chem 2005;280:26233–40.[Abstract/Free Full Text]
- Hough CD, Sherman-Baust CA, Pizer ES, et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 2000;60:6281–7.[Abstract/Free Full Text]
- Rangel LBA, Agarwal R, D'Souza T, et al. Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 2003;9:2567–75.[Abstract/Free Full Text]
- Hibbs K, Skubitz KM, Pambuccian SE, et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. Am J Pathol 2004;165:397–414.[Abstract/Free Full Text]
- Lu KH, Patterson AP, Wang L, et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res 2004;10:3291–300.[Abstract/Free Full Text]
- Santin AD, Zhan F, Bellone S, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer 2004;112:14–25.[CrossRef][Medline]
- Kominsky SL, Vali M, Korz D, et al. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol 2004;164:1627–33.[Abstract/Free Full Text]
- Long H, Crean CD, Lee WH, Cummings OW, Gabig TG. Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium. Cancer Res 2001;61:7878–81.[Abstract/Free Full Text]
- Gress TM, Muller-Pillasch F, Geng M, et al. A pancreatic cancer-specific expression profile. Oncogene 1996;13:1819–30.[Medline]
- Michl P, Buchholz M, Rolke M, et al. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology 2001;121:678–84.[CrossRef][Medline]
- Nichols LS, Ashfaq R, Iacobuzio-Donahue CA. Claudin 4 protein expression in primary and metastatic pancreatic cancer: support for use as a therapeutic target. Am J Clin Pathol 2004;121:226–30.[CrossRef][Medline]
- Sato N, Fukushima N, Maitra A, et al. Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol 2004;164:903–14.[Abstract/Free Full Text]
- Terris B, Blaveri E, Crnogorac-Jurcevic T, et al. Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol 2002;160:1745–54.[Abstract/Free Full Text]
- Michl P, Barth C, Buchholz M, et al. Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res 2003;63:6265–71.[Abstract/Free Full Text]
- Hoevel T, Macek R, Swisshelm K, Kubbies M. Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids. Int J Cancer 2004;108:374–83.[CrossRef][Medline]
- Agarwal R, D'Souza T, Morin PJ. Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res 2005;65:7378–85.[Abstract/Free Full Text]
- Cheung ST, Leung KL, Ip YC, et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clin Cancer Res 2005;11:551–6.[Abstract/Free Full Text]
- Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N. Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J Biol Chem 1997;272:26652–8.[Abstract/Free Full Text]
- Michl P, Gress TM. Bacteria and bacterial toxins as therapeutic agents for solid tumors. Curr Cancer Drug Targets 2004;4:689–702.[CrossRef][Medline]
- Santin AD, Cane S, Bellone S, et al. Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens enterotoxin. Cancer Res 2005;65:4334–42.[Abstract/Free Full Text]
- Hanna PC, Wnek AP, McClane BA. Molecular cloning of the 3' half of the Clostridium perfringens enterotoxin gene and demonstration that this region encodes receptor-binding activity. J Bacteriol 1989;171:6815–20.[Abstract/Free Full Text]
- Sonoda N, Furuse M, Sasaki H, et al. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 1999;147:195–204.[Abstract/Free Full Text]
- Offner S, Hekele A, Teichmann U, et al. Epithelial tight junction proteins as potential antibody targets for pancarcinoma therapy. Cancer Immunol Immunother 2005;54:431–45.[CrossRef][Medline]
- Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. Cancer Res 1999;59:5464–70.[Abstract/Free Full Text]
- Soini Y. Claudins 2, 3, 4, and 5 in Paget's disease and breast carcinoma. Hum Pathol 2004;35:1531–6.[CrossRef][Medline]
- Lee SK, Moon J, Park SW, Song SY, Chung JB, Kang JK. Loss of the tight junction protein claudin 4 correlates with histological growth-pattern and differentiation in advanced gastric adenocarcinoma. Oncol Rep 2005;13:193–9.[Medline]
- Borlak J, Meier T, Halter R, Spanel R, Spanel-Borowski K. Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours. Oncogene 2005;24:1809–19.[CrossRef][Medline]
- Morita K, Tsukita S, Miyachi Y. Tight junction-associated proteins (occludin, ZO-1, claudin-1, claudin-4) in squamous cell carcinoma and Bowen's disease. Br J Dermatol 2004;151:328–34.[CrossRef][Medline]
- Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, et al. Overexpression of the cell adhesion molecules DDR1, claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin Cancer Res 2004;10:4427–36.[Abstract/Free Full Text]
- Rangel LBA, Sherman-Baust CA, Wernyj RP, Schwartz DR, Cho KR, Morin PJ. Characterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expression. Oncogene 2003;22:7225–32.[CrossRef][Medline]
- Aldred MA, Huang Y, Liyanarachchi S, et al. Papillary and follicular thyroid carcinomas show distinctly different microarray expression profiles and can be distinguished by a minimum of five genes. J Clin Oncol 2004;22:3531–9.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
S. Mima, M. Takehara, H. Takada, T. Nishimura, T. Hoshino, and T. Mizushima
NSAIDs suppress the expression of claudin-2 to promote invasion activity of cancer cells
Carcinogenesis,
October 1, 2008;
29(10):
1994 - 2000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Angelow, R. Ahlstrom, and A. S. L. Yu
Biology of claudins
Am J Physiol Renal Physiol,
October 1, 2008;
295(4):
F867 - F876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Oshima, H. Miwa, and T. Joh
Aspirin induces gastric epithelial barrier dysfunction by activating p38 MAPK via claudin-7
Am J Physiol Cell Physiol,
September 1, 2008;
295(3):
C800 - C806.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Thakur, Y. Sun, A. Bollig, J. Wu, H. Biliran, S. Banerjee, F. H. Sarkar, and D. J. Liao
Anti-invasive and Antimetastatic Activities of Ribosomal Protein S6 Kinase 4 in Breast Cancer Cells
Clin. Cancer Res.,
July 15, 2008;
14(14):
4427 - 4436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Zhang, H.-P. Yao, and M.-H. Wang
Activation of RON differentially regulates claudin expression and localization: role of claudin-1 in RON-mediated epithelial cell motility
Carcinogenesis,
March 1, 2008;
29(3):
552 - 559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Van Itallie, L. Betts, J. G. Smedley III, B. A. McClane, and J. M. Anderson
Structure of the Claudin-binding Domain of Clostridium perfringens Enterotoxin
J. Biol. Chem.,
January 4, 2008;
283(1):
268 - 274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yano, T. Imaeda, and T. Niimi
Transcriptional activation of the human claudin-18 gene promoter through two AP-1 motifs in PMA-stimulated MKN45 gastric cancer cells
Am J Physiol Gastrointest Liver Physiol,
January 1, 2008;
294(1):
G336 - G343.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. C. Ip, S. T. Cheung, Y. T. Lee, J. C. Ho, and S. T. Fan
Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells
Mol. Cancer Ther.,
November 1, 2007;
6(11):
2858 - 2867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Wei and H. Li
A Markov random field model for network-based analysis of genomic data
Bioinformatics,
June 15, 2007;
23(12):
1537 - 1544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kuhn, M. Koch, T. Nubel, M. Ladwein, D. Antolovic, P. Klingbeil, D. Hildebrand, G. Moldenhauer, L. Langbein, W. W. Franke, et al.
A Complex of EpCAM, Claudin-7, CD44 Variant Isoforms, and Tetraspanins Promotes Colorectal Cancer Progression
Mol. Cancer Res.,
June 1, 2007;
5(6):
553 - 567.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Steinau, M. S. Rajeevan, D. R. Lee, M. T. Ruffin, I. R. Horowitz, L. C. Flowers, T. Tadros, G. Birdsong, M. Husain, D. C. Kmak, et al.
Evaluation of RNA Markers for Early Detection of Cervical Neoplasia in Exfoliated Cervical Cells
Cancer Epidemiol. Biomarkers Prev.,
February 1, 2007;
16(2):
295 - 301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lioni, P. Brafford, C. Andl, A. Rustgi, W. El-Deiry, M. Herlyn, and K. S.M. Smalley
Dysregulation of Claudin-7 Leads to Loss of E-Cadherin Expression and the Increased Invasion of Esophageal Squamous Cell Carcinoma Cells
Am. J. Pathol.,
February 1, 2007;
170(2):
709 - 721.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. DelloRusso, P. L. Welcsh, W. Wang, R. L. Garcia, M.-C. King, and E. M. Swisher
Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation
Mol. Cancer Res.,
January 1, 2007;
5(1):
35 - 45.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Davidson, Z. Zhang, L. Kleinberg, M. Li, V. A. Florenes, T.-L. Wang, and I.-M. Shih
Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from diffuse malignant peritoneal mesothelioma.
Clin. Cancer Res.,
October 15, 2006;
12(20):
5944 - 5950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. Yip, W. Shi, M. Pintilie, J. D. Martin, J. D. Mocanu, D. Wong, C. MacMillan, P. Gullane, B. O'Sullivan, C. Bastianutto, et al.
Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer.
Clin. Cancer Res.,
October 1, 2006;
12(19):
5726 - 5732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Holloway, D. S. Diyagama, K. Opeskin, J. Creaney, B. W.S. Robinson, R. A. Lake, and D. D.L. Bowtell
A Molecular Diagnostic Test for Distinguishing Lung Adenocarcinoma from Malignant Mesothelioma Using Cells Collected from Pleural Effusions
Clin. Cancer Res.,
September 1, 2006;
12(17):
5129 - 5135.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Honda, M. J. Pazin, H. Ji, R. P. Wernyj, and P. J. Morin
Crucial Roles of Sp1 and Epigenetic Modifications in the Regulation of the CLDN4 Promoter in Ovarian Cancer Cells
J. Biol. Chem.,
July 28, 2006;
281(30):
21433 - 21444.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Claudins Are Tight Junction...
