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PubMed1995

Pepsinogen C is a new prognostic marker in primary breast cancer.

PURPOSE: Here we evaluate in breast cancer patients the prognostic value of pepsinogen C, a proteolytic enzyme involved in the digestion of proteins in the stomach that is also synthesized by a significant percentage of breast carcinomas. PATIENTS AND METHODS: Pepsinogen C expression was examined by immunoperoxidase staining in a series of 243 breast cancer tissue sections, and results obtained were quantified using the HSCORE system, which considers both the intensity and the percentage of cells staining at each intensity. Evaluation of the prognostic value of pepsinogen C was performed retrospectively in corresponding patients by multivariate analysis that took into account conventional prognostic factors. The mean follow-up period was 48.5 months. RESULTS: A total of 113 carcinomas (46.5%) stained positively for this proteinase, but there were clear differences among them with regard to the intensity and percentage of stained cells. Pepsinogen C values were significantly higher in well differentiated (grade I, 89.1) and moderately differentiated (grade II, 88.5) tumors than in poorly differentiated (grade III, 27.7) tumors (P < .001). Similarly, significant differences in pepsinogen C content were found between estrogen receptor (ER)-positive tumors and ER-negative tumors (85.9 v 41.2, respectively; P < .05). Moreover, results indicated that low pepsinogen C content predicted shorter relapse-free survival duration and overall survival duration (P < .0001). Separate Cox multivariate analysis for relapse-free survival and overall survival in subgroups of patients as defined by node status showed that pepsinogen C expression was the strongest factor to predict both relapse-free survival and overall survival in node-positive patients (P < .0001 for both) and node-negative patients (P < .005 and P < .01, respectively). CONCLUSION: Pepsinogen C is a new prognostic factor for early recurrence and death in both node-positive and node-negative breast cancer. In addition, and in contrast to most studies that concern the prognostic significance of proteolytic enzymes in cancer, pepsinogen C production by breast cancer cells is associated with lesions of favorable evolution.

Adult↗
PubMed1993

Expression of pepsinogen C in human breast tumours and correlation with clinicopathologic parameters.

We have examined by immunohistochemistry the ability of breast carcinomas to produce pepsinogen C, an aspartyl proteinase usually involved in the digestion of proteins in the stomach. A total of 113 out of 245 breast tumours (46%) were positive for pepsinogen C immunostaining. There was a significant association between pepsinogen C and oestrogen receptors with proteinase levels higher (HSCORE) in oestrogen receptor positive tumours than in oestrogen receptor negative. There was also a significant association between pepsinogen C and histological grade, pepsinogen C levels being higher in well and moderately differentiated breast carcinomas than in poorly differentiated tumours. On the basis of these results, we suggest that pepsinogen C may be useful as a marker of good prognosis in breast cancer.

Adult↗
PubMed1996

Hormonal regulation of the human pepsinogen C gene in breast cancer cells. Identification of a cis-acting element mediating its induction by androgens, glucocorticoids, and progesterone.

Pepsinogen C is an aspartic proteinase mainly involved in the digestion of proteins in the stomach, which is also synthesized by certain human breast tumors. To examine the possibility that extragastric production of this proteolytic enzyme could be mediated by hormonal factors, we have analyzed pepsinogen C gene expression in human breast cancer cells subjected to different hormonal treatments. Northern blot analyses revealed the expression of pepsinogen C gene by T-47D breast cancer cells after induction with dihydrotestosterone, dexamethasone, and progesterone but not with estradiol, retinoic acid, or ethanol. Reverse transcription-polymerase chain reaction analysis in a series of breast cancer cell lines confirmed the amplification of pepsinogen C mRNA after induction with dihydrotestosterone, in those cells expressing the androgen receptor mRNA. The promoter region of the pepsinogen C gene was functionally characterized by transient expression of a vector containing the promoter region cloned in front of the chloramphenicol acetyltransferase (CAT) reporter gene. CAT activity in T-47D cells was stimulated in the presence of dihydrotestosterone, dexamethasone, and progesterone but not by estradiol. By further deletion mapping of the pepsinogen C promoter, a minimal region (AGAACTattTGTTCC) was identified as being responsible for glucocorticoid-, androgen-, and progesterone-regulated gene expression.

Base Sequence↗
PubMedDate not supplied

Expression and clinical significance of pepsinogen C in uveal melanomas.

PURPOSE: we investigated by immunohistochemistry the pepsinogen C (pepC) expression in uveal melanomas and analyzed the possible relationship to clinicopathological parameters and prognostic significance. METHODS: We studied 22 patients who had undergone enucleation of the eyeball or local tumor resection for uveal melanoma. The specimens were immunostained for pepC on formalin-fixed, paraffin-embedded sections. Sex, age, tumor location, histological type, local invasion, postoperative treatment and metastasis were evaluated. RESULTS: Eleven tumors (50%) were positive for pepsinogen C. The percentage of pepC-positive tumors was significantly higher in uveal melanomas with scleral invasion than in those without scleral invasion (p < 0.01). PepC expression was significantly associated with a shortened overall survival (p < 0.05). CONCLUSIONS: Our results show that pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors.

Adult↗
PubMedDate not supplied

Pepsinogen C expression in tumors of extragastric origin.

We have examined by immunohistochemistry the ability of human carcinomas of various origin to produce pepsinogen C, an aspartyl proteinase mainly involved in the digestion of proteins in the stomach and recently found to be associated with breast carcinomas. Of the 268 tumors analyzed 80 (29.8%) showed positive staining for pepsinogen C. These positive tumors included 12 gastric (38.7% of the 31 examined cases), nine pancreatic (42.8%), two renal (20%), 12 prostatic (40%), three bladder (27.3%), 14 endometrial (29.7%) and 18 ovarian (40%) carcinomas. We also detected 10 melanomas (50%) that were positive for pepsinogen C. By contrast, immunohistochemical staining for the proteinase was not detected in colorectal, cervical, lung and basal cell skin carcinomas. These results demonstrate that pepsinogen C, a proteolytic enzyme of highly restricted expression in human tissues, can also be expressed by a wide variety of human carcinomas. In addition, and similar to pepsinogen C expression in breast carcinomas, the production of this enzyme by different human tumors might be related to putative hormonal alterations associated with the development and progression of these tumors.

Biomarkers, Tumor↗
PubMed1966

Pepsinogen C and pepsin C. Further purification and amino acid composition.

Pepsinogen C and pepsin C from the pig have been further purified by chromatography on DEAE-cellulose and by exclusion chromatography and the specific activities (with haemoglobin substrate) found are higher than those previously reported. The final preparations are homogeneous on electrophoresis in starch gel at three pH values except for contamination with less than 4% of pepsinogen and pepsin respectively. Pepsinogen C, like pepsin C, contains no phosphate. The amino acid compositions show some marked differences from those of pepsinogen and pepsin especially in the content of basic amino acids, glutamic acid, aspartic acid, leucine and isoleucine. The molecular weights of the enzyme and zymogen, obtained from the amino acid compositions, are 41400 and 36000 respectively, similar to those of pepsinogen and pepsin.

Amino Acids↗
PubMed1987

Demonstration of pepsinogen C in human pancreatic islets.

Pancreatic tissue from 16 post mortem kidney donors have been examined for the content of pepsinogens. A zymogen with electrophoretic mobility, isoelectric point and molecular weight equal to that of pepsinogen C of gastric origin was found in all specimens. A comparison between pepsinogen C extracted from pancreatic tissue and gastric mucosa demonstrated immunological identity. Quantitative measurements with a radioimmunoassay showed pepsinogen C concentrations in pancreatic tissue three to 80 times higher than those of blood serum. Immunohistochemical staining gave positive reaction for pepsinogen C only in the alpha cells of the pancreatic islets.

Electrophoresis, Agar Gel↗
PubMed1989

Radioimmunoassay of human pepsinogen A and pepsinogen C.

We describe the development of radioimmunoassays to measure both human pepsinogen A and pepsinogen C concentrations in serum. The antibodies were raised in goats by immunization with purified pepsinogen A or C. The affinity constants of the respective antibodies were 20.10(10) l/mol and 7.10(10) l/mol. Pepsinogens A and C were labeled with Na 125I by the chloramine T method. The binding between labels and antibodies was inhibited by 0.50 at 0.82 ng pepsinogen A per tube and 2.1 ng pepsinogen C per tube. The detection limits of the assay of pepsinogen A and C were 0.12 microgram/l and 1.8 micrograms/l, respectively. Pepsinogen A and C were purified and added to a patient serum, showing a good recovery in the radioimmunoassays. Serial dilution of another patient serum, which contained a high concentration of both antigens, showed curves parallel to the standard curves. The intra- and interassay variations of these radioimmunoassays were evaluated. The intra-assay coefficients of variation for pepsinogen A were found to vary from 0.03 to 0.102 at concentrations in serum in the normal range, while the inter-assay coefficient of variation ranged from 0.118 to 0.194 at the same concentrations in serum. For the pepsinogen C radioimmunoassay we found intra-assay coefficients of variation between 0.126 and 0.147 at concentrations in serum in the normal range, while the inter-assay coefficient of variation ranged from 0.174 to 0.325 for the same sera. In 201 blood donors we found a mean serum concentration of pepsinogen A of 59 micrograms/l and a mean serum concentration of pepsinogen C of 15 micrograms/l. There was a significant relationship between these values (r = 0.779, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Achlorhydria↗
PubMed1993

Pepsinogen C gene polymorphisms associated with gastric body ulcer.

This study was aimed to investigate the association of restriction fragment length polymorphisms (RFLPs) for pepsinogen genes with peptic ulcer disease. Eighty unrelated controls, 61 patients with gastric ulcer, and 57 patients with duodenal ulcer were studied. No genetic polymorphisms for pepsinogen A were detected by EcoRI digestion in Japanese subjects but a 100 base pairs insertion-deletion RFLP for the pepsinogen C gene was observed. The allele frequencies of the large (3.6 kilobase EcoRI fragment) and the small fragment (3.5 kilobase EcoRI fragment) were 80.6% and 19.4% respectively in controls, 55.4% and 44.6% in patients with gastric body ulcer, 79.4% and 20.6% in patients with gastric angular ulcer, 71.4% and 28.6% in patients with gastric antral ulcer, and 75.4% and 24.6% in patients with duodenal ulcer. The allele frequency of the small fragment was significantly higher in patients with gastric body ulcer than in controls and in patients with gastric angular or antral ulcer. The genotypes which possessed the small fragment were significantly more frequent in patients with gastric body ulcer (78.4%) than in controls (33.8%) and in patients with gastric angular or antral ulcer (37.5%). These results suggest that there is a significant association between the genetic polymorphism at the pepsinogen C gene locus and gastric body ulcer, and that the pepsinogen C RFLP is a useful marker of the genetic predisposition to this disorder. These results also indicate genetic heterogeneity of gastric ulcer disease, and suggest that the pepsinogen C RFLP may be a useful subclinical marker to explain the differences in genetic aetiologies of gastric body ulcer and gastric angular or antral ulcer.

Adult↗
PubMed2003

Association between pepsinogen C gene polymorphism and genetic predisposition to gastric cancer.

AIM: To identify a molecular marker for gastric cancer, and to investigate the relationship between the polymorphism of pepsinogen C (PGC) gene and the genetic predisposition to gastric cancer. METHODS: A total of 289 cases were involved in this study. 115 cases came from Shenyang area, a low risk area of gastric cancer, including 42 unrelated controls and 73 patients with gastric cancer. 174 cases came from Zhuanghe area, a high-risk area of gastric cancer, including 113 unrelated controls, and 61 cases from gastric cancer kindred families. The polymorphism of PGC gene was detected by polymerase chain reaction (PCR) and the relation between the genetic polymorphism of PGC and gastric cancer was examined. RESULTS: Four alleles, 31 0bp (allele 1), 400 bp (allele 2), 450 bp (allele 3), and 480 bp (allele 4) were detected by PCR. The frequency of allele 1 was higher in patients with gastric cancer than that in controls. Genotypes containing homogenous allele 1 were significantly more frequent in patients with gastric cancer than that in controls (0.33, 0.14, chi(2)=3.86, P<0.05). There was no significant difference between the control group of Zhuanghe and the group of gastric cancer kindred. But the frequency of allele 1 was higher in control group of Zhuanghe area than that in control group of Shenyang area and genotypes containing homogenous allele 1 were significantly more frequent in the control group of Zhuanghe area than those in control group of Shenyang area (0.33, 0.14, chi(2)=4.32, P<0.05). In the group of gastric cancer kindred the frequency of allele 1 was significantly higher than that in control group of Shenyang area (0.5164, 0.3571, chi(2)=4.47, P<0.05). Genotypes containing homogenous allele 1 were significantly more frequent in the group of gastric cancer kindred than those in control group of Shenyang area (0.36, 0.14, chi(2)=4.91, P<0.05). CONCLUSION: These results suggest that there is some relation between pepsinogen C gene polymorphism and gastric cancer, and the person with homogenous allele 1 predisposes to gastric cancer than those with other genotypes. Pepsinogen C gene polymorphism may be used as a genetic marker for a genetic predisposition to gastric cancer. The distribution of pepsinogen C gene polymorphism in Zhuanghe, a high-risk area of gastric cancer, is different from that in Shenyang, a low risk area of gastric cancer.

Alleles↗
PubMed2001

Different effects of H. pylori water extracts on cytokines, pepsinogen C and gastrin mucosal release in patients with or without duodenal ulcer.

In the present study we ascertained whether cagA positive and negative H. pylori strains release water soluble products that can influence the production of gastric mucosal cytokines and endocrine (gastrin) or exocrine (pepsinogen C) secretion in 23 H. pylori positive and 19 H. pylori negative patients. Antral biopsies were obtained to classify inflammation, activity, atrophy, intestinal metaplasia and H. pylori density grade. The cagA gene was identified by means of the polymerase chain reaction (PCR) in H. pylori positive colonies after culture of mucosal samples. Three antral biopsies from each patient were incubated with (1.) Water extracts from cagA positive, (2.) Water extracts from cagA negative strains or (3.) H2O (control) at 37 degrees C in a CO2 incubator for 24 hrs. Gastrin, pepsinogen C, IL-1 beta, IL-8, GMCSF, and TNF alpha were measured in the supernatants and mucosal homogenates. H. pylori infection was significantly associated with an increased antral inflammation and activity (chi 2 = 21.7, p < 0.001 and chi 2 = 42.0, p < 0.001), and increased mucosal levels of IL-1 beta, IL-8 and TNF alpha. Water extracts from cagA positive strains enhanced the release of PGC in mucosal biopsy supernatants (p < 0.05) when patients were considered overall and the release of TNF alpha (p < 0.05) when only patients with duodenal ulcer were considered. Water extracts from cagA negative strains stimulated gastrin secretion (p < 0.05). None of the remaining cytokines were influenced by H. pylori water extracts. In conclusion, pepsinogen C and TNF alpha can be induced by cagA positive water extracts and may contribute to damage the gastric and duodenal mucosa. Our findings indicate that in patients with H. pylori infection the increase of the mucosal levels of IL-1 beta and IL-8 does not depend on H. pylori water soluble products, but probably depends on the entire bacterium.

Adult↗
PubMed1983

Identification of monkey lung procathepsin D-II as a pepsinogen-C-like acid protease zymogen.

Procathepsin D-II (Mr = 37 500) was purified from Japanese monkey lung at pH 7.0, and was shown to be converted to the active form, cathepsin D-II (Mr = 33 000) via an intermediate (Mr = 35 500) upon treatment at pH 3.0 and 14 degrees C. Procathepsin D-II was shown to be the inactive precursor of cathepsin D-II based on the following results: the former was inactive toward heat-denaturated casein at pH 5.4 whereas the latter was active; the former was not inactivated by diazoacetyl-DL-norleucine methyl ester in the presence of Cu2+ ion at pH 6.0 whereas the latter was inactivated rapidly under the same conditions; and the former had no affinity to pepstatin-Sepharose between pH 5 and 7 whereas the latter was adsorbed to it. With a rabbit antiserum against procathepsin D-II, cathepsin D-II, pepsinogen C and pepsin C of Japanese monkey were each found to give a single precipitin line which fused completely with each other on agarose plate. On the other hand, cathepsin D-I purified from the monkey lung, and pepsinogens A (I, II, III-1, III-2 and III-3) obtained from the monkey gastric mucosa failed to precipitate with the antiserum. With the antiserum against the monkey pepsinogen C, the same results were obtained. Further, procathepsin D-II and pepsinogen C were shown to have the same amino-terminal amino acid sequence, Ala-Val-Val-Lys-Val-Pro-Leu-Lys-Lys-Phe-Lys-. All these results indicate a strong similarity of procathepsin D-II and cathepsin D-II to pepsinogen C and pepsin C, respectively.

Amino Acids↗
PubMed1989

Human pepsinogen C (progastricsin). Isolation of cDNA clones, localization to chromosome 6, and sequence homology with pepsinogen A.

The entire pepsinogen C (PGC) coding sequence was determined by analysis of a series of five overlapping cDNA clones identified in a library constructed from human gastric mucosa poly(A+) RNA. A partial cDNA clone was initially identified using a 256-fold degenerate oligonucleotide probe for amino acid residues 4-12 of pepsin C, and subsequently 4 additional clones were identified upon rescreening with a probe complementary to the 5' region of the original cDNA clone. Northern analysis of gastric mucosa poly(A+) RNA with a PGC cDNA probe revealed an mRNA 1.5-kilobase species that was indistinguishable from that detected with a human pepsinogen A (PGA) cDNA probe. In contrast, the PGC and PGA cDNA probes detected distinct genomic restriction fragments indicating there was no detectable cross-hybridization under high stringency conditions. The PGC gene was localized to human chromosome 6 by analysis of a panel of human x mouse somatic cell hybrids. The regions containing the active site aspartyl groups of PGC are conserved in relationship to several other aspartic proteinases. We propose that the absence of detectable immunologic cross-reactivity between the two groups of human pepsinogens, A and C, results from divergent evolution of sequences located on the surface of the zymogens in contrast to the strongly conserved active site regions located within the binding cleft of the enzymes that are inaccessible for antigenic recognition.

Amino Acid Sequence↗
PubMed1989

Human pepsinogen C (progastricsin) polymorphism: evidence for a single locus located at 6p21.1-pter.

A series of six clones containing the entire human pepsinogen C gene (PGC) was identified in a cosmid vector library by using cDNA and oligonucleotide probes. The 10.7-kb PGC gene includes nine exons and exhibits a high degree of sequence identity (60%) with the functionally related pepsinogen A genes. The predicted amino acid sequence was identical with the partial amino-terminal and carboxyl-terminal sequences of purified pepsinogen C. An informative restriction fragment length polymorphism was detected with several restriction enzymes and involved an insertion or deletion of 100 bp of intron sequence located between exons 7 and 8. Evidence that there is only a single PGC gene in humans is presented. The PGC gene and the prolactin gene were regionally localized to 6p21.1-pter by analysis of mouse X human somatic cell hybrids.

Amino Acid Sequence↗
PubMed1999

A milk clotting assay for antibody using a fusion protein between protein A and pepsinogen C.

The proteolytic activity of a fusion protein between protein A and human pepsinogen C (PA-PGC) was measured by a modified milk clotting assay on 96-well microtiter plate. The assay ranges for 30 and 120 min-incubation were approximately 0.08-1.25 ng and 0.02-0.16 ng, respectively. Although the absorbance of milk solution decreased by the precipitation of clotted casein, the white precipitate was, if anything, convenient for an easy detection of reaction-positive wells. The borderline between the wells with or without precipitate was very clear and easily detected without the plate reader. This feature was thought to be suitable for the positive-negative judgment of a dilution test in enzyme immunoassay (EIA). Rabbit IgG adsorbed on a microtiter plate was then measured using PA-PGC and this milk assay (designated as PA-PGC assay). Although PA-PGC assay needed slightly longer incubation than the conventional color assay, the sensitivity of both systems was almost identical, and the reaction-positive wells containing white precipitate were easily detected at a very low range by the over night incubation without using the plate reader. PA-PGC assay possesses the unique and useful properties, and it can be used as a convenient and easy EIA technique.

Animals↗
PubMed1989

Assignment of human pepsinogen C (PGC) gene to chromosome 6.

cDNA of rat pepsinogen C (PGC) hybridizes to, among others, a 3.2-kb band in Southern blot analysis of BamHI-cleaved human genomic DNA. This property was employed to localize the human PGC gene. Use of flow-sorted human chromosomes and 12 human x mouse somatic cell hybrid lines demonstrated that the gene is located on chromosome 6.

Animals↗
PubMed2004

[Expression of pepsinogen C in gastric cancer and its precursor].

OBJECTIVE: To investigate the dynamic expression of pepsinogen C (PGC) and its value in detection of precursor and gastric cancer. METHODS: Immunohistochemistry was used to examine the expression of PGC in 424 biopsy specimens of stomach mucosa collected by gastroscopy. RESULTS: The positive rate of PGC expression in 54 cases of normal gastric mucosa was 100% and 2.4% in 124 cases of gastric cancer. The positive rate of PGC expression decreased in the order of superficial gastritis/gastric ulcer or erosion-->atrophic gastritis or gastric dysplasia-->gastric cancer (P < 0.01). CONCLUSION: The expression of PGC is negatively correlated with the degree of malignity of gastric mucosa and development of gastric lesions. PGC has high sensitivity and specificity in diagnosis of precursor of gastric cancer and can be a good indicator in the screening and diagnosis of precursor of gastric cancer and gastric cancer.

Adult↗
PubMed2006

Gastric cancer in a Caucasian population: role of pepsinogen C genetic variants.

AIM: To study the role of an insertion/deletion polymorphism in the pepsinogen C (PGC) gene, an effective marker for terminal differentiation of the stomach mucosa, in the susceptibility to the development of gastric lesions. METHODS: The study was performed with 99 samples of known gastric lesions and 127 samples without evidence of neoplastic disease. PCR was employed and the 6 polymorphic alleles were amplified: Allele 1 (510 bp), Allele 2 (480 bp), Allele 3/4 (450/460 bp), Allele 5 (400 bp) and Allele 6 (310 bp). RESULTS: Our results revealed that Allele 6 carriers seemed to have protection against the development of any gastric lesion (OR = 0.34; P<0.001), non-dysplastic lesions associated with gastric adenocarcinoma such as atrophy or intestinal metaplasia (OR = 0.28; P<0.001) or invasive GC (OR = 0.39; P = 0.004). CONCLUSION: Our study reveals that the Allele 6 carrier status has a protective role in the development of gastric lesions, probably due to its association with higher expression of PGC. Moreover, the frequency of Allele 6 carriers in the control group is far higher than that obtained in Asian populations, which might represent a genetic gap between Caucasian and Asian populations.

Alleles↗