Age-associated loss of heterozygosity of tumor suppressor genes in the gastric mucosa of humans

Lathika Moragoda1, Richard Jaszewski1,2, Prasad Kulkarni1, and Adhip P. N. Majumdar1,2,3,4

2 Veterans Affairs Medical Center, Departments of 1 Internal Medicine and 3 Biochemistry and Molecular Biology, and 4 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The current study is based on the hypothesis that aging predisposes gastric mucosa to carcinogenesis through altered expression and/or mutations of genes involved in cell growth. To test this hypothesis, we investigated the age-associated changes in mutation of adenomatous polyposis coli (APC), deleted in colorectal cancer (DCC), p53, and K-ras genes in the gastric mucosa of 19 healthy subjects of varying ages (25-91 yr). Specifically, we studied the loss of heterozygosity (LOH) of these genes in cardia, body, and antrum of the stomach. We observed that 3 of 19 subjects (16%) over 60 yr of age show LOH of at least one of the tumor suppressor genes. Among the subjects over 60 yr of age, the incidence of LOH is 38% (3/8). Two of three subjects had mutations in more than one tumor suppressor gene. In all three affected subjects, mutation in APC, DCC, or p53 was located mainly in the body of the stomach, suggesting increased susceptibility of this region to neoplastic changes. However, no LOH of K-ras was observed in these subjects. Our observation that subjects over 60 yr of age show mutation in one or more of the tumor suppressor genes suggests an age-related increase in predisposition of the stomach to neoplasia.

aging; mutations; p53; adenomatous polyposis coli; deleted in colorectal cancer; K-ras; neoplasia


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ALTHOUGH EARLIER OBSERVATIONS in the mouse suggest that proliferative activity of the small intestine either decreases (16, 24) or remains unchanged (17) with aging, recent morphological and biochemical studies from our own and other laboratories have demonstrated that in barrier-reared Fischer 344 rats, aging is associated with increased mucosal proliferative activity in the stomach and small and large intestines (3, 14, 21, 22, 27-29). In both gastric and colonic mucosa, the age-related rise in proliferation could partly be attributed to enhanced transition from G1 to S phase as well as progression through the S phase of the cell cycle (42, 44). Moreover, in the gastric mucosa, aging is also associated with increased activation of extracellular regulatory kinases and c-Jun NH2-terminal kinase and transcriptional activity of AP1 and nuclear factor kappa B (43). These changes are also accompanied by increased activation and expression of epidermal growth factor (EGF) receptor (37, 38). Overexpression of EGF receptor has been associated with many malignancies, including the colon and stomach (5, 6). These and other relevant observations have led to the postulation that aging may predispose the gastrointestinal tract to neoplasia (3, 23, 29).

Many probable reasons have been suggested for the age-dependent rise in malignancies, including altered carcinogen metabolism and cumulative effects of long-term exposure of cancer-causing agents (8, 10). The possibility that aging may render target cells more susceptible to carcinogenesis through mutation of tumor suppressor genes has not been investigated. Inactivation of tumor suppressor genes has been linked to the development and progression of carcinogenesis (25, 41).

The tumor suppressor gene p53 plays a crucial role in cellular proliferation and apoptosis and as the guardian of genomic integrity (4, 34). Similarly, the loss or inactivation of the tumor suppresser gene adenomatous polyposis coli (APC), which initiates genomic instability that may produce adenomas in the colon predisposing it to carcinogenesis, is well documented (11, 30). Mutation and loss of heterozygosity (LOH) of APC is also known for other cancers, including gastric cancer (33-36, 40). Similarly, deleted in colorectal cancer (DCC) is a tumor suppressor gene that has been shown to have allelic deletions and/or loss of expression in gastrointestinal and other carcinomas (13, 19). We have also studied K-ras, which is one of the protooncogenes most frequently mutated in many malignancies, including colorectal cancer, and is associated with increased uncontrolled cell proliferation (9).

One of the possibilities for the age-related rise in gastrointestinal cancers, particularly gastric cancer, could be that the rate of mutation(s) in tumor suppressor genes in the stomach increases with aging. To test this possibility, we have examined the incidence of mutation in p53, DCC, APC, and K-ras genes in different regions (cardia, body, and antrum) of the stomach during advancing age in humans. The reason for analyzing mutations in the cardia, body, and antrum is to determine whether and to what extent different regions of the stomach are affected by aging.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Biopsies. Patients aged more than 18 yr of age undergoing clinically indicated esophagogastroduodenoscopy (e.g., Hemoccult-positive stool, gastroesophageal reflux, iron deficiency anemia etc.) who were found to have macroscopically normal-appearing gastric mucosa were eligible to participate. Pairs of mucosal forcep biopsies were obtained from cardia, body, and antrum regions of the stomach and snap frozen in liquid nitrogen and stored at -80°C.

DNA extraction. Genomic DNA was extracted from each biopsy specimen using DNA Stat-60 reagent (Tel-Test, TX) according to the manufacturers protocol. Briefly, samples were homogenized in DNA Stat reagent and DNA precipitated from the aqueous phase using isopropanol.

Detection of LOH of p53. LOH in p53 was studied essentially according to the procedure described by Ara et al. (2). This method used restriction fragment length polymorphism (RFLP) exhibited by codon 72, which can be detected by restriction digestion with BstU1, following PCR amplification. Standard PCR reactions containing template DNA were denatured at 94°C for 1.5 min and amplified at 94°C for 40 s, 60°C for 40 s, and 72°C for 45 s for 40 cycles followed by extension at 72°C for 15 min. The primers used were sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' to amplify a 200-bp fragment. PCR products were digested with BstU1 (New England Biolabs) and separated on 2.5% agarose gels (FMC Bioproducts).

Detection of LOH of DCC. To study LOH of DCC, variable number of tandem repeats within the DCC gene (19, 26) was amplified. PCR reactions containing sample DNA were denatured at 94°C for 1.5 min and run at 94°C for 30 s, 58°C for 40 s, and 72°C for 40 s for 40 cycles followed by 15 min of extension at 72°C. The primers used were sense 5'-GATGACATTTTCCCTCTAG-3' and antisense-5'-GTGGTTATTGCCTTGAAAG-3' (26). The PCR products were separated on 2.5% agarose gels (FMC).

Detection of LOH of APC. LOH of APC was studied according to the procedure described by Tandle et al. (35). This method involves studying RFLP of APC in exon 11 by digesting with Rsa1 following PCR amplification. PCR reactions containing sample DNA were denatured first at 94°C for 1.5 min and amplified at 94°C for 40 s, 59°C for 40 s, and 72°C for 40 s for 35 cycles followed by 15 min of extension at 72°C. The primers were used were sense 5'-GGACTACAGGCCATTGCAGAA-3' and antisense 5'-GGCATCATCTCCAAAAGTCAA-3'. The amplified 133-bp fragment was digested with Rsa1 (NEB), and products were separated on 2.5% agarose gels.

Detection of LOH in K-ras. Mutations in K-ras were studied using the technique described by De Jong et al. (9). This technique detects a G-to-A transition, which creates a restriction site for HpH I in codon 12 of this gene. Briefly, PCR is performed using a mismatched primer pair [sense 5'-ACTTGTGGTAGTTGGAGGTG-3' (mismatch in bold) and antisense 5'-TCCACAAAGTGATTCTGAAT-3'] to generate a 75-bp product. The products were then digested with HpH I, which generates 46- and 26-bp bands if the gene is mutated. Wild-type products remain uncut by HpH I. PCR conditions used were identical to those described for APC amplification.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

To determine whether aging is associated with genetic changes in the gastrointestinal tract, incidence of mutations in p53, DCC, and APC genes, as assessed by LOH, was examined in biopsy specimens from different regions of the stomach (cardia, body, and antrum) in 19 subjects aged 25-91 yr (mean, 55.1) whose routine endoscopy revealed macroscopically normal appearing gastric mucosa (Table 1). Indications for upper endoscopy included gastroesophageal reflux disease (n = 10), nonulcer dyspepsia (n = 6), and Hemoccult-positive stools with negative colonoscopy and evidence of anemia (n = 3).

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   LOH analysis of p53, DCC, and APC genes in 19 healthy subjects of various ages

LOH of p53 was studied using the occurrence of RFLP in codon 72 of this gene (Fig. 1). Nine of nineteen subjects were homozygous, five of nine carried the allele for arginine (113- and 86-bp bands) and four of nine carried the allele for proline (199-bp band). Of the 10 subjects who were heterozygous, one subject, age 64 yr, showed LOH of p53 (Fig. 1). This LOH was observed only in the body of the stomach but not in the other two regions.


View larger version (44K):
[in this window]
[in a new window]
 
Fig. 1.   Representative figure showing loss of heterozygosity (LOH) analysis of p53. Heterozygous condition is indicated by the presence of all 3 bands. Homozygous individuals have either a 199-bp band or 113- and 86-bp bands. LOH is shown by a 64-yr-old subject in the body. A, antrum; B, body; C, cardia; M, DNA marker.

With respect to DCC, we observed eight homozygous individuals having either a 200-bp allele or a 160-bp allele and 11 heterozygous individuals with both alleles (Fig. 2). Two of the heterozygous individuals showed alleles that were larger than the normal 200-bp allele and smaller than the 160-bp allele (Fig. 2, lane 8). These size differences may be due to insertions or deletions. However, these deviations were observed in all three regions of the stomach and hence, were not considered as age-associated mutations. LOH in DCC was observed in 10% (2/19) of the subjects whose ages were 64 and 91. Interestingly, the 64-yr-old individual was the same subject who exhibited LOH in p53 (Table 1 and Fig. 2, lane 6). In the 91-yr-old subject, both DCC alleles were observed to be lost in the body, although both alleles were present in cardia and antrum (Fig. 2, lane 9). Similar to what we observed for p53, LOH in DCC was also detected in the body of the stomach.


View larger version (58K):
[in this window]
[in a new window]
 
Fig. 2.   Representative figure showing LOH analysis of the deleted in colorectal cancer gene. Heterozygous individuals have both 200- and 160-bp bands, whereas homozygous individuals show either the 200- or 160-bp band. LOH is shown by 64- and 91-yr-old subjects in the body.

In the case of APC, 11 individuals were observed to be heterozygous, possessing the 133-bp band corresponding to an allele uncut with Rsa1 and 85- and 68-bp bands representing alleles cut with Rsa1. The rest were homozygous, having either cut or uncut allele (Fig. 3). Interestingly, the 91-yr-old subject, who was homozygous with respect to antrum and cardia, showed a gain of heterozygosity in the body region (Fig. 3). This may be explained by the occurrence of a mutation at the restriction site of one allele, thus rendering this site unavailable for cutting. A similar phenomenon was observed with a 72-yr-old subject who showed homozygosity with respect to body and cardia but heterozygosity with respect to antrum (Fig. 3). Both of these patients had histologically normal gastric mucosa without evidence of Helicobacter pylori infection.


View larger version (106K):
[in this window]
[in a new window]
 
Fig. 3.   Representative figure showing LOH analysis of the adenomatous polposis coli gene. Heterozygous condition is indicated by the presence of all 3 bands. Homozygous individuals have either a 133-bp or 87- and 46-bp bands. LOH is observed in the 91- and 72-yr-old subjects in the body and antrum, respectively.

Investigation of K-ras gene, on the other hand, revealed no mutations in codon 12 in the cardia, antrum, or main body of the stomach of any subject (data not shown). Codon 12 was selected to analyze mutational status of K-ras, because this region is considered to be most relevant to the progression of colorectal cancer.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Aging is associated with many gastrointestinal dysfunctions (20, 23). One of the most consistent pathological observations in senescent animals is increased incidence of many types of malignancies, including gastric and colorectal cancers. Gastric cancer rarely occurs before the age of 40 yr, but its incidence increases subsequently, with peak incidence occurring in the seventh decade. Many probable reasons, including altered carcinogen metabolism and long-term exposure of cancer-causing agents, have been offered for the age-dependent rise in malignancies (8, 10).

Carcinogenesis, which is a multistep process, results from the accumulation of mutations during progression from normal epithelium to carcinoma (12). Genetic changes that occur at different stages of epithelial cell carcinoma have been extensively studied by Vogelstein and colleagues (11) in human colon cancer. At least for colon cancer, it has been suggested that the loss or inactivation of the tumor suppressor gene APC initiates genomic instability that may produce phenotypic appearance of an adenoma. The advanced tumors, however, possess mutations and/or deletion of a number of oncogenes and tumor-suppressor genes not seen in early adenoma (7, 11, 12). Although such detailed analysis of genetic alterations has not been performed for gastric cancer, inactivation of several tumor suppressor genes, including APC, p53, and DCC, has been observed in gastric cancer (1, 39, 45) and inactivation of K-ras in the case of colorectal cancer (9). However, to the best of our knowledge, no information is available whether aging, which is thought to predispose the gastrointestinal tract to carcinogenesis, is associated with increased inactivation of tumor suppressor genes.

Our current data, for the first time, show that in humans, the incidence of mutations of several tumor suppressor genes, specifically APC, DCC, and p53 in the gastric mucosa, is higher in older subjects. We have observed that 3 of 19 subjects (16%) who are over 60 yr of age show LOH of APC, DCC, or p53 gene in the body of the stomach. However, among the subjects over 60 yr of age, the rate of this incidence is 38% (3/8). This rise in mutations of tumor suppressor genes among the older subjects could not be accounted for by the presence of cancer in the stomach or any other organ. None of the subjects were diagnosed with any type of cancer or precancerous lesions at the time of endoscopy or were treated for these symptoms earlier. Foci of atrophic gastritis typically coalesce, resulting in a state of reduced gastric acid that may progress to chronic atrophic gastritis and associated intestinal metaplasia. These lesions are thought to be most closely associated with the subsequent development of dysplasia and carcinoma (18). Although some of the subjects had mild gastritis, this condition could not be related to LOH of the tumor suppressor genes, because the three subjects who demonstrated LOH of one of the tumor suppressor genes were devoid of this symptom. More importantly, none of our study subjects with genetic aberrations had gastric mucosal evidence of intestinal metaplasia, atrophic gastritis, or H. pylori infection, each of which is thought to be associated with the development of gastric cancer (31, 32). Finally, none of our study patients had clinical evidence of pernicious anemia or a history of gastric surgery, conditions known to predispose to gastric carcinogenesis (18). Although mutational activation of K-ras protooncogene is widely implicated in the development and progression of colorectal cancer (15), we observed no mutations of this protooncogene in the gastric mucosa of any of the subjects. Thus, unlike the tumor suppressor genes, aging does not appear to induce mutations of the protooncogene K-ras.

Although gastric carcinoma occurs in all regions of the stomach, we have observed that the majority (4/5) of mutations are located in the body of the stomach. The reason for this is not fully understood. One plausible explanation could be that with aging, the body of the stomach, which is primarily composed of parietal cells, becomes more susceptible to genetic alterations. Whether this is the result of prolonged exposure to endogenous acid or exogenous noxious agents remains to be determined.

Interestingly, two of three subjects who show mutations also show mutation in more than one gene. Although the reasons for this are not fully understood, one plausible explanation could be that they may possess defective DNA repair mechanisms. Another possibility could be due to inherent genetic susceptibility of tumor suppressor genes to mutations and to endogenous and/or exogenous noxious agents. Undoubtedly, further detailed analysis with a larger number of subjects is needed to gain an understanding in this and other related matters.


    ACKNOWLEDGEMENTS

The work was supported by grants to Dr. Majumdar from the Dept. of Veterans Affairs and the National Institute on Aging (AG-14343).


    FOOTNOTES

Address for reprint requests and other correspondence: A. P. N. Majumdar, Research Service-151, VA Medical Center, 4646 John R, Detroit, MI 48201 (E-mail: a.majumdar{at}wayne.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published January 30, 2002;10.1152/ajpgi.00312.2001

Received 16 July 2001; accepted in final form 24 January 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Abraham, SC, Nobukawa B, Giardiello FM, Hamilton SR, and Wu T. Fundic gland polyps in familial polyposis: neoplasms with frequent somatic adenomatous polyposis coli. Am J Pathol 157: 747-754, 2000[Abstract/Free Full Text].

2.   Ara, S, Lee PSY, Hansen MF, and Saya H. Codon 72 Polymorphism of the TP53 gene. Nucleic Acids Res 18: 4961, 1990[ISI][Medline].

3.   Atillasoy, E, and Holt PR. Gastrointestinal proliferation and aging. J Gerontol 48: B43-B49, 1993[ISI][Medline].

4.   Baker, SJ, Fearon ER, Nigro JM, Hamilton SR, Prisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y, Kinzler KW, and Vogelstein B. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244: 217-221, 1989[ISI][Medline].

5.   Barnard, JA, Beauchamp J, Russell WE, Dubois RN, and Coffey RJ. Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology 108: 564-580, 1995[ISI][Medline].

6.   Bennett, C, Paterson IM, Corbisgley CM, and Luqman YA. Expression of growth factor and epidermal growth factor receptor encoded transcripts in human gastric tissues. Cancer Res 49: 2104-2111, 1989[Abstract].

7.   Boland, CR, Sinicrope FA, Brenner DE, and Caretghers JM. Colorectal cancer prevention and treatment. Gastroenterology 118: S115-S128, 2000[ISI][Medline].

8.   Burnett, FM. The concept of immunological surveillance. Prog Exp Tumor Res 13: 1-27, 1970[ISI][Medline].

9.   De Jong, T, Skinner SA, Malcontenti-Wilson C, Vogiagis D, Bailey M, Van Driel IR, and O'Brian PE. Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation. Am J Physiol Gastrointest Liver Physiol 278: G266-G272, 2000[Abstract/Free Full Text].

10.   Dilman, VM. Ageing, metabolic immunodepression and carcinogenesis. Mech Ageing Dev 8: 153-173, 1978[ISI][Medline].

11.   Fearon, ER, and Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61: 759-767, 1990[ISI][Medline].

12.   Fearon, ER. Genetic alterations underlying colorectal tumorigenesis. Cancer Surv 12: 119-136, 1992[ISI][Medline].

13.   Fearon, ER, Cho KR, Nigro JM, Kern SE, Simons JW, Rupport JM, Hamilton SR, Prisinger AC, Thomas G, Kinzler KW, and Vogelstein B. Identification of a chromosome 18q gene that is altered in colorectal carcinoma. Science 247: 49-56, 1990[ISI][Medline].

14.   Fligiel, SEG, Relan NK, Dutta S, Tureaud J, Hatfield J, and Majumdar APN Aging diminishes gastric mucosal regeneration: relationship to tyrosine kinases. Lab Invest 70: 764-774, 1994[ISI][Medline].

15.   Forrester, K, Almoguera C, Han K, Grizzle WE, and Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327: 298-303, 1987[ISI][Medline].

16.   Fry, RJM, Lesher S, and Kohn H. Age effect on cell-transit time of the mouse jejunal epithelium. Am J Physiol 201: 213-216, 1961[ISI].

17.   Fry, RJM, Lesher S, and Kohn H. Influence of age on the transit time of cells in the mouse epithelium. Lab Invest 11: 289-293, 1962[ISI].

18.   Fuchs, CS, and Mayer RJ. Gastric carcinoma. N Engl J Med 333: 32-41, 1995[Free Full Text].

19.   Gao, X, Hohn KV, Grignon D, Sakr W, and Chen YQ. Frequent loss of expression and loss of heterozygosity of the putative tumor suppreossor gene DCC in prostatic carcinomas. Cancer Res 53: 2723-2727, 1993[Abstract].

20.   Geokas, MC, Conteas CN, and Majumdar APN The aging gastrointestinal tract, liver and pancreas. In: Clinics in Geriatric Medicine, edited by Geokas MC.. Philadelphia: Saunders, 1985, vol. 1, p. 177-205.

21.   Holt, PR, and Yeh KY. Colonic proliferation is increased in senescent rats. Gastroenterology 95: 1556-1563, 1988[ISI][Medline].

22.   Holt, PR, and Yeh KY. Small intestinal crypt cell proliferation rates are increased in senescent rats. J Gerontol 44: B9-B14, 1989[ISI][Medline].

23.   Jaszewski, R, Ehrinpreis MN, and Majumdar APN Aging and cancer of the stomach and colon. Front Biosci 4: 322-328, 1999.

24.   Lesher, S, Fry RJM, and Kohn HI. Age and the generation time of the mouse duodenal epithelium cell. Exp Cell Res 24: 331-413, 1988.

25.   Levine, LA, Momad J, and Finlay CA. The p53 tumor suppressor gene. Nature 351: 453-456, 1991[ISI][Medline].

26.   Maesawa, C, Tamura G, Suzuki Y, Ogasawara S, Sakata K, Kashiwaba M, and Sotodate R. The sequential accumulation of genetic alterations chracteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma. J Pathol 176: 249-258, 1995[ISI][Medline].

27.   Majumdar, APN, and Arlow FL. Aging: altered responsiveness of gastric mucosa to epidermal growth factor. Am J Physiol Gastrointest Liver Physiol 257: G554-G560, 1989[Abstract/Free Full Text].

28.   Majumdar, APN, Jasti S, Hatfield JS, Tureaud J, and Fligiel SEG Morphological and biochemical changes in gastric mucosa of aged rats. Dig Dis Sci 35: 1364-1370, 1990[ISI][Medline].

29.   Majumdar, APN, Jaszewski R, and Dubick MA. Effect of aging on the gastrointestinal tract and pancreas. Proc Soc Exp Biol Med 215: 134-144, 1997[Abstract].

30.   Miyoshi, Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, and Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region of the APC gene. Hum Mol Genet 1: 229-233, 1992[Abstract].

31.   Nomura, A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, and Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325: 1132-1136, 1991[Abstract].

32.   Ohkusa, T, Kazuhiko F, Takashimizu I, Kumagal J, Tanizawa T, Eishi Y, Yokoyama T, and Watanabe M. Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann Intern Med 134: 380-386, 2001[Abstract/Free Full Text].

33.   Pecina-Slaus, N, Pavelic KJ, and Pavelic L. Loss of Heterozygosity of APC gene in renal cell carcinomas. J Mol Med 77: 446-453, 1999[ISI][Medline].

34.   Rhyu, MG, Park WS, Jung YJ, Choi SW, and Meltzer SJ. Allelic deletions in of MCC/APC and p53 are frequent late events in human gastric carcinogenesis. Gastroenterology 106: 1584-1588, 1994[ISI][Medline].

35.   Tandle, A, Sanghavi V, and Saranath D. Infrequent loss of heterozygosity at adenomatous polyposis coli gene locus in Indian oral cancers. Cancer Lett 157: 155-160, 2000[ISI][Medline].

36.   Thompson, AM, Morris RG, Wallace M, Wyllie AH, Steele CM, and Carter DC. Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. Br J Cancer 68: 64-68, 1993[ISI][Medline].

37.   Tureaud, J, Sarkar F, Fligiel SEG, Kulkarni S, Jaszewski R, Reddy K, Yu Y, and Majumdar APN Increased expression of EGFR in gastric mucosa of aged rats. Am J Physiol Gastrointest Liver Physiol 273: G389-G398, 1997[Abstract/Free Full Text].

38.   Turner, JD, Liu L, Fligiel SEG, Jaszewski R, and Majumdar APN Aging alters gastric mucosal responses to epidermal growth factor and transforming growth factor alpha . Am J Physiol Gastrointest Liver Physiol 278: G805-G810, 2000[Abstract/Free Full Text].

39.   Uchino, S, Tsuda H, Noguchi M, Yokota J, Terada M, Saiton T, Kobayashi M, Sugimura T, and Hirohashi S. Frequent loss of heterozygosity at DCC locus in gastric Cancers. Cancer Res 52: 3099-3122, 1992[Abstract].

40.   Weiland, I, and Bohm M. Frequent allelic deletion at a novel locus on chromosome 5 in human lung cancer. Cancer Res 54: 1772-1774, 1994[Abstract].

41.   Weinberg, RA. Tumor suppressor gene. Science 254: 1138-1146, 1991[ISI][Medline].

42.   Xiao, ZQ, Jaszewski R, and Majumdar APN Aging enhances G1 to S phase transition in the colonic mucosa. Mech Ageing Dev 116: 1-14, 2001[ISI].

43.   Xiao, ZQ, and Majumdar APN Induction of transcriptional activity of AP1 and NF-kappa B in the gastric mucosa during aging. Am J Physiol Gastrointest Liver Physiol 278: G855-G865, 2000[Abstract/Free Full Text].

44.   Xiao, ZQ, Yu Y, Khan A, Jaszewski R, Ehrinpreis MN, and Majumdar APN Induction of G1 checkpoint in the gastric mucosa of aged rats. Am J Physiol Gastrointest Liver Physiol 277: G917-G921, 1999[Abstract/Free Full Text].

45.   Yokozaki, H, Yasui W, and Tahara E. Genetic and epigenetic changes in stomach cancer. Int Rev Cytol 204: 49-95, 2001[ISI][Medline].


Am J Physiol Gastrointest Liver Physiol 282(6):G932-G936




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
282/6/G932    most recent
00312.2001v1
Alert me when this article is cited
Alert me if a correction is posted
Citation Map
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Search for citing articles in:
ISI Web of Science (4)
Google Scholar
Articles by Moragoda, L.
Articles by Majumdar, A. P. N.
Articles citing this Article
PubMed
PubMed Citation
Articles by Moragoda, L.
Articles by Majumdar, A. P. N.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online