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Expression of Bax protein in gastric carcinomas. A clinicopathological and immunohistochemical study

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Abstract

Reduced Bax protein expression has been shown to be a negative prognostic factor in patients with breast, ovarian, colorectal, esophageal and pancreatic cancer. Our aim was to immunohistochemically study Bax protein expression in gastric carcinomas and correlate its expression with clinicopathological parameters and prognosis. Immunohistochemistry was performed, using a monoclonal antibody against bax, in paraffin-embedded tumor specimens from 47 cases of gastric cancer. Positive staining for the Bax protein was found in 20/47 (42.4%) adenocarcinomas examined. Negative Bax protein expression in tumour cells was correlated with lymph node metastasis (P < 0.05), and degree of differentiation (p < 0.05). Univariate analysis showed that the variables with a significant negative impact on survival were: high TNM tumour stage, depth of penetration in the gastric wall, lymph node involvement, and Bax protein expression. Multivariate analysis showed that the only variable with an impact on survival was Bax protein expression (p < 0.05, Relative Risk: 3.34). Kaplan-Meier curves showed that the 5-year survival was 36.8% in cases with positive compared with 16% in cases with negative Bax protein expression (p = 0.0427). Negative Bax expression in gastric cancer is associated with de-differentiation, lymph node metastases, and poor clinical prognosis. Bax protein expression might play an important role in the development and phenotypic differentiation of gastric carcinomas and tumor progression.

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... This finding indicated that p53 mutations usually occur before invasion during breast cancer progression, and that p53 protein expression in DCIS is an important indicator of cancer invasiveness and prognosis of DCIS. 13 In agreement with Kayaselcuk et al, 15 who found positive correlation between bcl-xl expression and grade of DCIS. This controversy reflects the complexity of bax and bcl-xl regulation and the need for more studies for these genes on both immunohistochemical and molecular levels. ...
... 37 This indicates that regulation of bax is complex, and may be explained by the presence of p53 mutations which affect its interaction with bax protein, or by intervention of other molecules which may modulate the function of either or both proteins. 36 In the current study, negative correlation between bax and bcl-2 expression was detected in DCIS (p < 0.01), which concurs with Kapucuoglu et al, (1997), 38 who found that while both proteins were expressed at the same time in normal and benign epithelium, different staining patterns were observed according to the degree of differentiation of the neoplastic epithelium. ...
... ,14 bcl-2 expression was not correlated with the grade of DCIS, which suggests that alterations in bcl-2 expression in breast carcinoma are more prominent in invasive rather than in in situ lesions.In agreement with Rehman et al, (2000),15 and Kayaselcuk et al, (2004),14 who found that bax expression did not correlate with increasing histological grades of DCIS, we found insignificant correlation between bax expression and tumor grade of DCIS. Contradictory findings were obtained byKapucuoglu et al, (1997) 16 and Anagnostopoulos et al, (2007), 17 who found that bax protein expression in DCIS was related to more aggressive neoplasms. ...
... This finding indicated that p53 mutations usually occur before invasion during breast cancer progression, and that p53 protein expression in DCIS is an important indicator of cancer invasiveness and prognosis of DCIS. 13 In agreement with Kayaselcuk et al, 15 who found positive correlation between bcl-xl expression and grade of DCIS. This controversy reflects the complexity of bax and bcl-xl regulation and the need for more studies for these genes on both immunohistochemical and molecular levels. ...
... 37 This indicates that regulation of bax is complex, and may be explained by the presence of p53 mutations which affect its interaction with bax protein, or by intervention of other molecules which may modulate the function of either or both proteins. 36 In the current study, negative correlation between bax and bcl-2 expression was detected in DCIS (p < 0.01), which concurs with Kapucuoglu et al, (1997), 38 who found that while both proteins were expressed at the same time in normal and benign epithelium, different staining patterns were observed according to the degree of differentiation of the neoplastic epithelium. ...
... ,14 bcl-2 expression was not correlated with the grade of DCIS, which suggests that alterations in bcl-2 expression in breast carcinoma are more prominent in invasive rather than in in situ lesions.In agreement with Rehman et al, (2000),15 and Kayaselcuk et al, (2004),14 who found that bax expression did not correlate with increasing histological grades of DCIS, we found insignificant correlation between bax expression and tumor grade of DCIS. Contradictory findings were obtained byKapucuoglu et al, (1997) 16 and Anagnostopoulos et al, (2007), 17 who found that bax protein expression in DCIS was related to more aggressive neoplasms. ...
... Bcl-2 was not correlated to tumor size in our study, which is consistent with the findings of Eguchi et al. (2000) and Tsutsui et al. (2006), and This finding suggests that there may be a balance between anti-apoptotic and antiproliferative activity of bcl-2 in breast carcinoma, so that the net effect of bcl-2 on tumor size is abolished. On the other hand, Anagnostopoulos et al. (2007) found positive correlations between bcl-2 expression and smaller tumor size. This difference may be explained by variable co-expression of bcl-2 with other molecules that affect tumor size e.g p53, Ki-67, or other bcl-2 family members. ...
... This controversy reflects the complexity of bax regulation and the need for more studies for this gene on both immunohistochemical and molecular levels to clarify its role (Rehman et al., 2000). Concurring with Anagnostopoulos et al. (2007), this study showed positive correlation between bax expression and tumor grade of IBC (p<0.05). ...
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One of the greatest challenges in breast cancer management is to accurately predict the outcome for each patient. To do this at present, we rely heavily on traditional pathological variables, such as tumor size, tumor grade and lymph node status. However, despite the broad applicability of clinic-pathological indices, they are still unable, to separate the 30% node-negative patients who will relapse from the 70% who will not. We aimed to: 1. Study the immunohistochemical profile of bcl-2 and bax in breast carcinoma. 2. Assess their prognostic values in relations to clinico-pathological prognostic factors. Subjects and methods: This study included 45 specimens of breast carcinoma. Patient’s age, tumor size and local aggressive changes, history of recurrence and/or presence of distant metastasis were obtained. Sections stained with H&E were evaluated for the presence of benign breast disease, tumor type and tumor grade, presence of in situ component, lymphocytic infiltration, lymphovascular invasion and axillary lymph node status. Immunostaining was done to detect the expression of bcl-2 and bax. Results: Both bcl-2 and bax were regularly expressed in areas of benign breast disease. Bcl-2 was positive in all ductal carcinoma in situ (DCIS); 100% of grade I, 89% of grade II and 87% of grade III invasive breast carcinoma (IBC). Bcl-2 was inversely correlated to tumor grade of IBC (p<0.03) and to lymphocytic infiltration (p<0.02). Bax was positive in (80%) low grade, (100%) intermediate and high grade DCIS. Bax was positive in (83%) grade I IBC and in all (100%) grade II and grade III IBC. Bax expression was positively correlated to: tumor grade (p<0.05) and lymphocytic infiltration (p<0.00). No significant difference in either bcl-2 or bax expression in lymph nodal positive or negative cases. In DCIS; negative correlation was present between bcl-2 and bax (p<0.01). In IBC; insignificant correlation was present between bcl-2 and bax. Conclusions: Bcl-2 is an indicator for good prognosis in breast cancer being negatively correlated to tumor grade and prominent lymphocytic infiltration. Bax is an indicator for poor prognosis in breast cancer being positively correlated to tumor grade and presence of prominent lymphocytic infiltration.
... 12.7–67%, 42.4–58.0%, 23.5– 72.9%, respectively [9,12,2223242526. p53 played an important role in apoptosis. ...
... This result was different from a previous research. Anagnostopoulos et al. [24] reported that negative bax expression in gastric was associated with lymph node metastasis and poor clinical prognosis. The reasons for the conflicting results were not clear. ...
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... In the TCGA database, the expression of PCNA in gastric carcinoma tissues is higher than that in normal tissues, further confirming that downregulation of PCNA levels can inhibit gastric carcinoma cells proliferation. In addition, Anagnostopoulos GK et al. found that low expression of Bax in gastric carcinoma was associated with low 5-year survival and poor clinical prognosis [21]. ...
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Bulbus Lilii, as a medicinal and edible plant, has anti-inflammatory, anti-oxidative and immunopotentiating pharmacological activities, which seems to be therapeutic on cancer prevention. The purpose of this study was to investigate the effects of total saponins from Lilium lancifolium (TSLL) on proliferation, apoptosis and migration of human gastric carcinoma cells lines SGC-7901 and HGC-27 and its underlying mechanism. The results showed that TSLL inhibited the proliferation of gastric carcinoma cells by suppressing the level of proliferating cell nuclear antigen (PCNA) and increased p21 level. TSLL induced cells apoptosis by up-regulating expression of pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2 expression. Meanwhile, TSLL remarkably inhibited cell migration and invasion, decreased matrix metalloproteinase-2 (MMP-2) expression and increased tissue inhibitor of metalloproteinases-1 (TIMP-1) expression. Notably, TSLL had stronger anti-cancer effect on undifferentiated HGC-27 cells than differentiated SGC-7901 cells. Accordingly, TSLL might be a promising candidate to prevent and suppress the growth of gastric carcinoma cells.
... 26 Notwithstanding the variable expression of BAX in gastric carcinomas, 28 its status may be suggestive of its role being played in the development and evolution of this type of malignant tumors, since BAX-negativity has been related to shorter survival periods of patients surgically treated for their disease. 50 As regards the relatively novel member of the BCL-2 family, the BCL2L12 gene, 30 its peculiar attributes as either a pro-survival 31,32,51 or pro-apoptotic 33,34,[36][37][38]52 factor have been a pole of attraction for constant research endeavors. In fact, a series of data has demonstrated the usefulness of BCL2L12 expression in human solid tumors, including stomach apoptosis. ...
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... Regarding GC, the role of BAX has been studied mainly in patients undergoing curative resection, in order to show a potential correlation with pathological characteristics and risk of disease relapse and death. In small retrospective series, decreased BAX expression was strongly associated with dedifferentiation, lymph node metastases, diffuse histology and poor clinical outcome [23,24]. Recently, the largest surgical series of 501 resected GC patients failed to show any significant correlation of BAX with prognosis, while BCL2 expression was significantly and independently associated with better outcome [25]. ...
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... The prognostic role of BAX was mainly studied in series of patients with GC who underwent curative surgery. It was correlated to unfavourable pathological features such as diffuse-type, poor differentiation or lymph node metastases, leading to a poor clinical outcome in terms of disease relapse and death (58,59). At present, few data have been published about the prognostic or predictive role of BAX in advanced gastro-oesophageal cancer treated with chemotherapy. ...
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Currently, therapeutic management of gastric cancer is mainly based on clinical data and histological features. Although several new treatment options have recently been introduced, inter-individual variability of response and drug resistance are still a challenge. Many promising markers have been identified to predict prognosis and likelihood of response to therapy, in order to tailor treatment regimens on the basis of patients' individual features. However, despite recent developments in gene sequencing and molecular diagnostics, many biomarkers still have a controversial role. Published data are often contradictory and at the moment, no molecular marker, other than Human epidermal growth factor receptor-2 (HER2) status for trastuzumab-based treatment, has entered the mainstream of clinical practice. The primary obstacle to the identification of reliable markers lies in technical difficulties in quantitatively assessing molecular alterations; genome-wide analyses are also often misleading due to the complexity of biological processes. Nevertheless, many biomarkers are being evaluated in clinical trials in order to identify criteria for stratifying patients and establish customized therapeutic approaches. In this review, we provide an update on promising biological prognostic and predictive markers, with a focus on growth factor signalling molecules, DNA repair systems, fluoropyrimidine metabolism and apoptotic pathways.
... In a surgical series of 57 resected gastric cancer specimens, a strong relationship between decreased Bax expression and diffuse-type gastric or poorly differentiated morphology was identified [16]. Bax-negative expression was associated with dedifferentiation, lymph node metastases, and poor clinical prognosis in a different series of 47 resected gastric cancer [17] . Moreover, the role of the low expression of Bax as a poor prognostic factor has been reported in several malignancies treated with chemotherapy or chemoradiotherapy, such as breast, ovarian, and head and neck cancer181920 . ...
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... BAX gene encodes a protein belonging to the BCL family members. Negative BAX protein expression has been associated with de-differentiation, lymph node metastasis and shorter survival, suggesting that BAX status may play a role in the development and differentiation of gastric cancer and tumor progression [99] . ...
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Aspirin- and non-steroidal anti-inflammatory drug (NSAID)-induced apoptosis is one of the important mechanisms for their anti-tumour effect in gastric cancer. We aimed at determining the role of bcl-2 family proteins and caspases in the apoptotic process. Gastric cancer cell lines AGS (wild-type p53) and MKN-28 (mutant p53) were used. Cell proliferation was measured by MTT assay. Apoptosis was determined by acridine orange staining. Protein expressions were determined by western blotting. Aspirin and indomethacin inhibited cell proliferation and induced apoptosis in both cells. AGS cells were more sensitive compared with MKN-28 cells. The pro-apoptotic proteins bax and bak were overexpressed after treatment, while the protein level of bcl-2 remained unchanged. Apoptosis was accompanied by an increase in caspase-3 activity and cleavage of caspase-3 and poly(ADP-ribose) polymerase. Inhibition of caspase-3 rescued aspirin-induced apoptosis. Our results suggest that one of the major pathways which mediates the anti-tumour response of aspirin and indomethacin in gastric cancer cells is through up-regulation of bax and bak and activation of caspase-3. Bax and bak are important in the chemoprevention of gastric cancer.
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Background/Aims:Helicobacter pylori induces the apoptosis of gastric epithelial cells in vivo and in vitro. However, the molecular mechanism has not been clarified. The aim of this study was to investigate the effect of H pylori on the apoptosis of gastric epithelial cells and the expression of apoptosis related genes in vitro. Methods: Human gastric adenocarcinoma SGC-7901 cells were co-cultured with a cytotoxic H pylori strain, NCTC 11637, at various densities ranging from 3.2 × 104 to 1.0 × 108 colony forming units (CFU)/ml for 48 hours. Apoptosis in gastric cells was determined by transmission electron microscopy, Hoechst 33258 fluorochrome staining, and flow cytometry. The expression of apoptosis related proteins, Bcl-2, Bax, and c-Myc, was measured by an immunohistochemical method, and c-Myc mRNA expression was determined by the reverse transcription-polymerase chain reaction. Results:Helicobacter pylori induces morphological changes typical of apoptosis. Both fluorochrome staining and flow cytometry showed that the apoptotic index began to increase when H pylori were at a density of > 1.6 × 104 CFU/ml, and in a density dependent manner (p < 0.01; one way ANOVA). The expression of the Bax and c-Myc proteins and of c-Myc mRNA was increased, whereas Bcl-2 expression was decreased after co-culture for 48 hours. Conclusions:Helicobacter pylori induced apoptosis in gastric epithelial cells is mediated by altered expression of the products of the Bcl-2, Bax, and c-Myc genes.
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ApoptosisThree separate research groups report in this issue of Science ([pages. 782][1],[784][2], andp. [787][3]) that a cellular protein called nuclear factor kappa B (NF-κ B)blocks the programmed form of cell suicide known as apoptosis in several cell types. This finding has led to the suggestion that blocking NF-κ B in tumor cells might make them more vulnerable to drugs or radiation. [1]: /lookup/doi/10.1126/science.274.5288.782 [2]: /lookup/doi/10.1126/science.274.5288.784 [3]: /lookup/doi/10.1126/science.274.5288.787
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REVIEW A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.
Article
The execution phase of apoptosis is comprised of those processes that commit cells to apoptotic death. Many independent studies have implicated mitochondria as playing a critical role in apoptotic execution. The activation of caspase-3 and subsequent late stage degradative events are probably triggered by the release of proteins (such as cytochrome c) from the intermembrane space of mitochondria. The mechanisms responsible for this release are controversial but may include mitochondrial permeability transition and bcl-2-regulated swelling of the mitochondrial matrix. Two theoretical models of execution are discussed. It is important to note that some critical features of these models are largely based on data acquired from cell-free studies. Further studies with intact cells are urgently needed to test the physiological validity of these models.
Article
Proapototic gene is an important target to enhance the chemotherapeutic effect in cancer cells. Based on in vitro study showing that the introduction of bax gene enhanced the sensitivity to anticancer drugs, we examined whether the intratumoral administration of bax gene could enhance the anti-tumor effect in combination with anticancer drugs in gastric cancer. The human gastric cancer cell line, MKN45 was transplanted into nude mice, and the intratumoral administration of bax gene was performed using the bax cDNA plasmid complexed with a cationic lipopolyamine. The enhancement of antitumor effect was examined in the combination with 5-fluorouracil (5-FU) and cisplatin (CDDP). The anticancer drugs were administered intraperitoneally with one third of LD50 four times at 4-day intervals, and the antitumor effect was assessed by the NCI protocol. The expression of bax gene was analyzed by RT-PCR and the apoptotic cell death was assessed by TUNEL method. The intratumoral administration of bax gene alone showed slight anti-tumor effect as compared to that of control tumor injected with vector alone. The antitumor effect of 5-FU and CDDP was significantly enhanced in the combination with intra-tumoral administration of bax gene as compared to that of CDDP and 5-FU alone (p<0.05, Student's t-test). The enhancement of antitumor effect was associated with the constitutive overexpression of bax gene and with the induction of apoptosis in the tumor treated with anticancer drug and bax gene. These results indicate that the combination therapy of intratumoral administration of bax gene complexed with a cationic lipopolyamine and anticancer drugs may provide us a new strategy for cancer chemotherapy to enhance its therapeutic efficacy in gastric cancer as termed with gene-chemotherapy.
Article
Bcl-2 family proteins are key regulators of programmed cell death or apoptosis that is implicated in many human diseases, particularly cancer. In recent years, they have attracted intensive interest in both basic research to understand the fundamental principles of cell survival and cell death and drug discovery to develop a new class of anticancer agents. The Bcl-2 family includes both anti- and pro-apoptotic proteins with opposing biological functions in either inhibiting or promoting cell death. High expression of anti-apoptotic members such as Bcl-2 and Bcl-XL commonly found in human cancers contributes to neoplastic cell expansion and interferes with the therapeutic action of many chemotherapeutic drugs. The functional blockade of Bcl-2 or Bcl-XL could either restore the apoptotic process in tumor cells or sensitize these tumors for chemo- and radiotherapies. This article reviews the recent progress in the design and discovery of small molecules that block the anti-apoptotic function of Bcl-2 or Bcl-XL. These chemical inhibitors are effective modulators of apoptosis and promising leads for the further development of new anticancer agents.
Article
Two major intracellular apoptosis signaling cascades have been characterized, the mitochondrial pathway and the death receptor pathway. The mitochondrial pathway is regulated by members of the Bcl-2 protein family. The members of this family can be subdivided into anti- and pro-apoptotic proteins. The pro-apoptotic members are further divided into two groups, the multidomain and the 'BH3 domain only' proteins. When cells are exposed to apoptotic stimulation, pro-apoptotic proteins are activated through post-translational modifications or changes in their conformation. The main site of action of the multidomain proteins are the mitochondria, where these proteins induce permeabilization of the outer membrane resulting in the release of proteins, including cytochrome c, from the intermembrane space. In the cytosol cytochrome c activates caspase cascades ultimately leading to cell death. Mounting evidence indicates that apoptosis is involved in a wide range of pathological conditions. Recent studies suggest that the mitochondrial signaling pathway is involved in several diseases. Although, so far, with the exception of C. elegans, most studies on apoptosis have been performed in mammalian systems, recently homologues to the Bcl-2 family members, including pro-apoptotic members, have been identified in Drosophila and zebrafish. Here the structure and function of the various pro-apoptotic Bcl-2 family members, their effects on mitochondria, and their involvement in diseases are discussed.
Article
AIM:To study the expression of proapoptotic gene Bax in human gastric carcinoma and its significance.METHODS:Using immunohistochemistry methods, the Bax protein expression in 57 specimens of gastric carcinoma and its relationship with clinical status and pathomorphological parameters were observed.RESULTS:Thirty- three (57.9%) cases were positive for Bax protein staining which was mainly located in the cytoplasm of tumor cells. The rate of Bax protein expression was not correlated with the tumor size, lymph node metastasis, depth of invasion, clinical stages of tumors and age and sex of patients (P >0.05), but strongly associated with the morphological type and differentiation degree of tumors. It was significantly higher in intestinal type and well or moderately differentiated gastric carcinoma than in diffuse type and poorly differentiated gastric carcinoma (P < 0.05 and P <0.01).CONCLUSION:The proapoptotic gene Bax is differently expressed in most of gastric carcinoma and may take part in the modulation of apoptosis in gastric carcinoma. The expression of Bax might be associated with the occurrence of intestinal type gastric carcinoma and the differentiation of gastric carcinoma.
Article
Seminal studies on the proto-oncogene bcl-2 have first demonstrated that mutations that inhibit programmed cell death (apoptosis) can promote lymphomagenesis and influence the sensitivity of tumour cells to chemotherapy or radiotherapy. It is now widely believed that neoplastic transformation of many, perhaps even all, cell types requires mutational changes that interfere with the cell death programme. In this review, we describe current knowledge of the molecular control of cell death and discuss the role of pro- and anti-apoptotic members of the Bcl-2 protein family in tumourigenesis and anti-cancer therapy.
Article
Products of the arachidonic acid metabolizing enzyme, 5-lipoxygenase (5-LOX), stimulate the growth of several cancer types. Inhibitors of 5-LOX and 5-LOX-activating protein (FLAP) induce apoptosis in some cancer cells. Here, the authors investigated the effect of a FLAP inhibitor, MK-886, on the inhibition of proliferation and induction of apoptosis in gastric cancer. Cell proliferation in gastric cancer cells was measured using an 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was measured using acridine orange staining and flow cytometry. Protein expression of apoptosis-related genes p53, p21waf1, p27kip1, bcl-2 families, cytochrome c, and the caspases were examined using Western blotting. Caspase-3 activity was measured using colorimetric assay of substrate cleavage. MK-886 inhibited cell growth in a dose- and time-dependent manner. Apoptosis was induced in gastric cancer cells and was characterized by upregulation of p27kip1 and bax, with release of cytochrome c from mitochondria into cytosol, which initiated caspase-3 activation. Specific caspase-3 inhibitors partially blocked MK-886-induced apoptosis. The present results suggest that MK-886 induces apoptosis in gastric cancer cells through upregulation of p27kip1 and bax, and that MK-886 is a potentially useful drug in gastric cancer prevention and therapy.
Article
Bcl-2 protein prolongs cell survival in the face of classical apoptotic stimuli, and is considered to be a suppressor of apoptosis. Bax plays a key role in apoptosis by accelerating cell death after an apoptotic stimulus. The aim of our study was to determine the roles of the Bax proapoptotic gene and the Bcl-2 antiapoptotic gene in the carcinogenesis of gastric cancer. One hundred and forty-five gastric biopsy specimens of chronic gastritis, atrophic gastritis, intestinal metaplasia and gastric dysplasia were studied. Using immunohistochemical methods, Bax and Bcl-2 protein expression was observed. Bax was expressed in epithelial cells in all cases of chronic gastritis. Bax was not detected in 26% of specimens of atrophic gastritis. As intestinal metaplasia develops, Bax is further suppressed. In biopsy samples with dysplasia, Bax expression was demonstrated only in 12% of biopsy samples. Although Bcl-2 protein was not detected in chronic gastritis, aberrant expression was found in gastric epithelial intestinal metaplasia and dysplasia. The suppression of Bax and overexpression of Bcl-2 protein is an early event in gastric tumorigenesis, before gastric dysplastic changes occur.
Article
Apoptosis proteins may play a role in prognosis and therapy response; however, they have not been fully investigated in gastric cancer. We aimed to assess the expression of proteins in the Bcl-2 family. Immunohistochemistry was employed to examine the expression of the antiapoptotic proteins Bcl-2 and Bcl-XL and the proapoptotic proteins Bad, Bak, Bax, Bid, Bim, and p53 in 21 cases of gastric cancer. Immunopositivity was observed in 12/21 (57%) cases for p53, 16/21 (76%) cases for Bcl-XL, and 5/21 (23%) cases for Bcl-2. For the proapoptotic members of the Bcl family, loss of protein expression was observed: Bid (14/21 cases; 66%), Bad (13/21 cases; 61%), Bax (12/21 cases; 57%), Bak (9/21 cases; 42%), and Bim (4/21 cases; 19%). This study identified apoptosis proteins that exhibit heterogeneous expression between primary gastric carcinomas.
Article
Evasion of apoptosis is one of the hallmarks of cancer. Bax-interacting factor-1 (Bif-1) interacts with both Bax and Bak that are essential for the intrinsic pathway of apoptosis, and enhances apoptosis. The aim of this study was to explore whether alteration of Bif-1 expression might be a characteristic of gastric cancer. We analysed the expression of Bif-1 protein in 60 gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach. In normal gastric mucosal cells, surface and glandular epithelial cells strongly expressed Bif-1. While Bif-1 expression was detected in 24 cases (40%) of the gastric carcinomas, there was no Bif-1 immunostaining in the remaining 36 cancers. Even in the 24 cases with positive Bif-1 immunostainings, 10 cancers showed decreased intensity of immunostaining compared with the normal mucosal epithelial cells. The decreased expression of Bif-1 in malignant gastric epithelial cells compared with the normal mucosal cells suggests that loss of Bif-1 expression may play a role in gastric tumorigenesis, possibly by inhibiting the apoptosis mediated by Bif-1.
Article
Matrine, one of the main active components from the dry roots of Sophora flavescence, was known to induce apoptosis in a variety of tumor cells in vitro. However, the molecular mechanism of cell apoptosis induced by Matrine remains elusive. Here, we investigated the apoptosis in Matrine-treated human gastric cancer MKN45 cells. The results showed that Matrine could inhibit cell proliferation and induce apoptosis in a dose-dependent manner. Further immunoblots revealed that in Matrine-treated cells, caspase-3, -7 were activated and the pro-apoptotic molecules Bok, Bak, Bax, Puma, and Bim were also up-regulated. Our results suggested that Matrine induced gastric cancer MKN45 cells apoptosis via increasing pro-apoptotic molecules of Bcl-2 family.
Article
Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/PGK-GV16+Ad/GT-Bax: Ad/Bax). To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53. The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/Bax or Ad/p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/Bax and Ad/p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment. Treatment with Ad/Bax and Ad/p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/p53 and only treatment with Ad/Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/p53 treatment. Ad/Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.