p53 is important for the anti-invasion of ganoderic acid T in human carcinoma cells.

11th Friday, 2012  |   Herb or Compound  |  no comments

p53 is important for the anti-invasion of ganoderic acid T in human carcinoma cells.

Chen NH, Zhong JJ. Phytomedicine. 2011 Jun 15;18(8-9):719-25. Epub 2011 Feb 25.

The function of p53 induced by ganoderic acids (GAs) in anti-invasion was unknown, although our previous work reported the inhibition of tumor invasion and metastasis by Ganoderic acid T (GA-T). This work indicated that GA-T promoted cell aggregation, inhibited cell adhesion and surpressed cell migration with a dose-dependent manner in human colon tumor cell lines of HCT-116 p53(+/+) and p53(-/-). Furthermore, comparing the ratios of HCT-116 p53(+/+) and p53(-/-) cells, p53 modified GA-T inhibition of migration and adhesion and GA-T promotion of cell aggregation, and p53 also modified GA-T inhibition of NF-?B nuclear translocation, I?B? degradation, and down-regulation of urokinase-type plaminogen activator (uPA), matrix metalloproteinase-2/9 (MMP-2/9), inducible nitric oxide synthase (iNOS/NOS2) protein expression and inducible nitric oxide (NO) production. The results indicated that p53 played an important role in anti-invasion of GA-T in human carcinoma cells. p53 may be an important target for GA-T inhibiting human carcinoma cells anti-invasion.

Ganodermanontriol, a lanostanoid triterpene from Ganoderma lucidum, suppresses growth of colon cancer cells through ß-catenin signaling.

Jedinak A, Thyagarajan-Sahu A, Jiang J, Sliva D. Int J Oncol. 2011 Mar;38(3):761-7. doi: 10.3892/ijo.2011.898. Epub 2011 Jan 11.
Colorectal cancer is one of the most common cancers in men and women in the world. Previous molecular studies have revealed that deregulation of the ß-catenin signaling pathway plays a crucial role in the progression of colorectal cancer. Therefore, modulation of the ß-catenin pathway offers a strategy to control colorectal cancer progression. The medicinal mushroom Ganoderma lucidum (GL) is a rich source of triterpenes with anticancer properties. Here, we show that ganodermanontriol (GNDT), a purified triterpene from GL, inhibited proliferation of HCT-116 and HT-29 colon cancer cells without a significant effect on cell viability. Moreover, GNDT inhibited transcriptional activity of ß-catenin and protein expression of its target gene cyclin D1 in a dose-dependent manner. A marked inhibition effect was also seen on Cdk-4 and PCNA expression, whereas expression of Cdk-2, p21 and cyclin E was not affected by the GNDT treatment. In addition, GNDT caused a dose-dependent increase in protein expression of E-cadherin and ß-catenin in HT-29 cells. Finally, GNDT suppressed tumor growth in a xenograft model of human colon adenocarcinoma cells HT-29 implanted in nude mice without any side-effects and inhibited expression of cyclin D1 in tumors. In conclusion, our data suggest that ganodermanontriol might be a potential chemotherapeutic agent for the treatment of cancer.

Triterpenes from Ganoderma Lucidum induce autophagy in colon cancer through the inhibition of p38 mitogen-activated kinase (p38 MAPK).

Thyagarajan A, Jedinak A, Nguyen H, Terry C, Baldridge LA, Jiang J, Sliva D. Nutr Cancer. 2010;62(5):630-40.
Medicinal mushroom Ganoderma lucidum is one of the most esteemed natural products that have been used in the traditional Chinese medicine. In this article, we demonstrate that G. lucidum triterpene extract (GLT) suppresses proliferation of human colon cancer cells HT-29 and inhibits tumor growth in a xenograft model of colon cancer. These effects of GLT are associated with the cell cycle arrest at G0/G1 and the induction of the programmed cell death Type II-autophagy in colon cancer cells. Here, we show that GLT induces formation of autophagic vacuoles and upregulates expression of Beclin-1 (1.3-fold increase) and LC-3 (7.3-fold increase) proteins in colon cancer cells and in tumors in a xenograft model (Beclin-1, 3.9-fold increase; LC-3, 1.9-fold increase). Autophagy is mediated through the inhibition of p38 mitogen-activated protein kinase (p38 MAPK) because p38 MAPK inhibitor, SB202190, induces autophagy and expression of Beclin-1 (1.2-fold increase) and LC-3 (7.4-fold increase), and GLT suppresses phosphorylation of p38 MAPK ( approximately 60% inhibition) in colon cancer cells. Taken together, our data demonstrate a novel mechanism responsible for the inhibition of colon cancer cells by G. lucidum and suggest GLT as natural product for the treatment of colon cancer.

Ganoderic acid T inhibits tumor invasion in vitro and in vivo through inhibition of MMP expression.

Chen NH, Liu JW, Zhong JJ. Pharmacol Rep. 2010 Jan-Feb;62(1):150-63.
The traditional Chinese medicinal mushroom, Ganoderma lucidum, has been used in Asia for several thousand years for the prevention and treatment of a variety of diseases, including cancer. In previous work, we purified ganoderic acid T (GA-T) from G. lucidum [28]. In the present study, we investigate the functions of GA-T in terms of its effects on invasion in vitro and metastasis in vivo. A trypan blue dye exclusion assay indicates that GA-T inhibits proliferation of HCT-116 cells, a human colon carcinoma cell line. Cell aggregation and adhesion assays show that GA-T promotes homotypic aggregation and simultaneously inhibits the adhesion of HCT-116 cells to the extracellular matrix (ECM) in a dose-dependent manner. Wound healing assays indicate that GA-T also inhibits the migration of HCT-116 cells in a dose-dependent manner, and it suppresses the migration of 95-D cells, a highly metastatic human lung tumor cell line, in a dose- and time-dependent manner. In addition, GA-T inhibits the nuclear translocation of nuclear factor-kappaB (NF-kappaB) and the degradation of inhibitor of kappaB-alpha (IkappaBalpha), which leads to down-regulated expression of matrix metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), and urokinase-type plasminogen activator (uPA). Animal and Lewis Lung Carcinoma (LLC) model experiments demonstrate that GA-T suppresses tumor growth and LLC metastasis and down-regulates MMP-2 and MMP-9 mRNA expression in vivo. Taken together, these results demonstrate that GA-T effectively inhibits cancer cell invasion in vitro and metastasis in vivo, and thus it may act as a potential drug for treating cancer.

Effects of Ganoderma lucidum on apoptotic and anti-inflammatory function in HT-29 human colonic carcinoma cells.

Hong KJ, Dunn DM, Shen CL, Pence BC. Phytother Res. 2004 Sep;18(9):768-70.
Ling Zhi extract (LZE) is a herbal mushroom preparation which been used world wide for the prevention and treatment of various cancers. The current study was designed to evaluate these claims in human colon cancer cells in terms of cancer preventive mechanisms. Results have demonstrated induction of apoptosis, anti-inflammatory action and differential cytokine expression during induced inflammation in the human colonic carcinoma cell line, HT-29. LZE caused no cytotoxicity in HT-29 cells at doses less than 10,000 microg/ml. Increasing concentrations of LZE reduced prostaglandin E2 production, but increased nitric oxide production. LZE treatment induced apoptosis by increasing the activity of caspase-3. RT-PCR showed that LZE at a concentration of 5000 microg/ml decreased the expression of cyclooxygenase-2 mRNA. Among 42 cytokines tested by protein array in this study, supplementation of LZE at doses of 500 and 5000 microg/ml to HT-29 cells reduced the expression of interleukin-8, macrophage inflammatory protein 1-delta, vascular epithelial growth factor, and platelet-derived growth factor. These results suggest that LZE has pro-apoptotic and anti-inflammatory functions, as well as inhibitory effects on cytokine expression during early inflammation in colonic carcinoma cells, which may be of significance in the use of Chinese herbal alternative medicines for cancer prevention.

Isoflavone aglycon produced by culture of soybean extracts with basidiomycetes and its anti-angiogenic activity.

Miura T, Yuan L, Sun B, Fujii H, Yoshida M, Wakame K, Kosuna K. Biosci Biotechnol Biochem. 2002 Dec;66(12):2626-31.
Soybean extracts (SBE) containing isoflavone glycosides were cultured with Ganoderma lucidum mycelia producing beta-glucosidase. The anti-angiogenic effects of the cultivated product, containing rich in genistein, named GCP (genistein combined polysaccharide), were assessed with chick chorioallantoic membranes (CAM) and a mouse dorsal air-sac model. Beta-glucosidase produced by the mycelia converted the isoflavone glycosides into aglycons. A test of volunteers showed that serum concentrations of genistein in the subjects treated with GCP (n = 4) at 3 h after administration were significantly higher than those in the subjects treated with SBE (n = 4). GCP inhibited angiogenesis in CAM, and the activity of GCP was greater than that of SBE. GCP inhibited the formation of new vessels induced by colon carcinoma cells in vivo.

A water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia suppresses azoxymethane-induction of colon cancers in male F344 rats.

Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H. Oncol Rep. 2003 Mar-Apr;10(2):375-9.
The present study was designed to investigate the protective effect of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (designated as MAK) on the induction and development of azoxymethane (AOM)-induced colon tumors in male F344/Du Crj rats. A total of 80 animals were divided into five groups at six weeks of age, groups 2, 3 and 4 being given weekly subcutaneous injections of AOM (15 mg/kg body weight) for the initial 3 weeks to induce colon tumors. Rats in group 1 and 5 were injected with the vehicle, 0.9% (w/v) saline, following the same schedule. Rats in groups 1, 2, 3, 4 and 5 were fed MF, MF, 1.25% MAK, 2.5% MAK and 2.5% MAK diets, respectively, starting 1 week before AOM treatment and throughout the six-month experimental period. There were no significant differences in number of ACF, total AC and AC per site among groups 2 to 4, but the tumor incidence was significantly lower, and tumor size was smaller in group 4 (AOM + 2.5% MAK) than in group 2 (AOM + MF). Additionally, beta-catenin positive tumor cell nuclei were significantly decreased in the MAK-fed rats (groups 3 and 4), which also demonstrated lowering of the PCNA labeling index and a shortened germinal region in the colon. The present results thus indicate that dietary MAK could act as a potent chemopreventive agent for colon carcinogenesis.

Prevention of development of N,N’-dimethylhydrazine-induced colon tumors by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male ICR mice.

Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H. Int J Mol Med. 2002 Feb;9(2):113-7.
The protective effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (designated as MAK) against development of colon tumors were investigated in male ICR mice. The animals were given weekly injections of N,N’-dimethylhydrazine (DMH, 10 mg/kg body weight) for the initial 10 weeks to induce colon carcinogenesis, and then fed on diet with or without 5% MAK for 10 weeks. There were no significant differences in incidence and the total number of colon tumors between the groups. However, the MAK diet group demonstrated significantly reduced sizes of tumors in comparison with the MF diet group. Moreover, this was linked to a lowered PCNA positive index and shortening of the germinal region in the colon. beta-catenin positive tumor cell nuclei were also significantly decreased in the MAK group. The present results thus indicate that dietary MAK could act as a potent chemopreventive agent for colon carcinogenesis.

Prevention of the development of preneoplastic lesions, aberrant crypt foci, by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male F344 rats.

Lu H, Uesaka T, Katoh O, Kyo E, Watanabe H. Oncol Rep. 2001 Nov-Dec;8(6):1341-5.
The modifying effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (MAK) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for three weeks to induce ACF and fed on diets containing 0, 1.25, 2.5 and 5.0% MAK for five weeks, starting one week before the first dose of carcinogen. MAK significantly and dose-dependently prevented the development of ACF, decreasing the total number of AC and inhibiting cyst formation. MAK (2.5 and 5.0%) also significantly reduced the longitudinal-cross section areas of colon epithelium. MAK in all doses significantly reduced the PCNA positive index, area of the germinal region and number of cells per half crypt. In an additional in vitro experiment, MAK inhibited anchorage-independent growth of several colon carcinoma cell lines. The present results thus indicate that dietary MAK could act as a preventive agent for colon carcinogenesis.

Assessment of anti-angiogenic and anti-tumoral potentials of Origanum onites L. essential oil.

10th Thursday, 2012  |   Herb or Compound, Lung Cancer  |  no comments


Medicinal plants and culinary herbs with anti-angiogenic and little toxicity properties have gained importance. Non-toxic anti-angiogenic phytochemicals are useful in combating cancer by preventing the formation of new blood vessels to support the tumor growth. We have investigated the essential oil of Origanum onites L. (OOEO), for a possible anti-angiogenic activity. OOEO was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The anti-proliferative activities (by MTT assay, 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide), anti-angiogenic activities (by tube formation assay), cell migration inhibiting capability (migration assay) and apoptotic potential (DAPI staining) of OOEO were evaluated on rat adipose tissue endothelial cells (RATECs) and 5RP7 (c-H-ras transformed rat embryonic fibroblasts) cells. Our results revealed that OOEO could markedly inhibit cell viability and induced apoptosis of 5RP7 cells and also could block in vitro tube formation and migration of RATEC. These results imply that OOEO having anti-angiogenic activity might be useful in preventing angiogenesis-related diseases and in combating cancer.
SOURCE:
Bostancıoğlu RB, Kürkçüoğlu M, Başer KH, Koparal AT. Food Chem Toxicol. 2012 Apr 3;50(6):2002-2008. [Epub ahead of print]

Effects of Carvacrol on a Human Non-Small Cell Lung Cancer (NSCLC) Cell Line, A549

Carvacrol, the predominant monoterpene in many essential oils of Labitae including Origanum, Satureja, Thymbra, Thymus, and Corydothymus has substantial antibacterial, antifungal, antihelmintic, insecticial, analgesic and antioxidant activities. Approximately 75% of lung cancer is non-small cell carcinoma (NSCLC) which comprises several histologic types squamous cell, adenocarcinoma and large cell carcinoma. It was reported that the portion of lung tumors diagnosed as denocarcinoma has increased. Thus a human non-small cell lung cancer (NSCLC) cell line, A549 was chosen for this study.
To investigate the effects of carvacrol on cell morphology, apoptosis and total protein amount, the cells incubated with various concentration of carvacrol in DMSO for 24 h. In carvacrol applied A549 cell line, increase in dose of carvacrol caused a decrease in cell number, degeneration of cell morphology and a decrease in total protein amount. To characterize carvacrol induced changes in cell morphology, cells were examined by light microscopy. Cells were treated with carvacrol were seen to have detached from the disk, with cell rounding, cytoplasmic blebbing and irregularity in shape. The data demonstrate that carvacrol is very potent inhibitor of cell growth in A549 cell line.
SOURCE:
Koparal AT, Zeytinoglu M. Cytotechnology. Volume 43, Numbers 1-3 (2003), 149-154, DOI: 10.1023/B:CYTO.0000039917.60348.45

Bisphenol A alters the development of the rhesus monkey mammary gland

10th Thursday, 2012  |   Herb or Compound  |  no comments

Tharp AP, Maffini MV, Hunt PA, et al. PNAS May 7, 2012, doi: 10.1073/pnas.1120488109

The xenoestrogen bisphenol A (BPA) used in the manufacturing of various plastics and resins for food packaging and consumer products has been shown to produce numerous endocrine and developmental effects in rodents. Exposure to low doses of BPA during fetal mammary gland development resulted in significant alterations in the gland’s morphology that varied from subtle ones observed during the exposure period to precancerous and cancerous lesions manifested in adulthood. This study assessed the effects of BPA on fetal mammary gland development in nonhuman primates. Pregnant rhesus monkeys were fed 400 μg of BPA per kg of body weight daily from gestational day 100 to term, which resulted in 0.68 ± 0.312 ng of unconjugated BPA per mL of maternal serum, a level comparable to that found in humans. At birth, the mammary glands of female offspring were removed for morphological analysis. Morphological parameters similar to those shown to be affected in rodents exposed prenatally to BPA were measured in whole-mounted glands; estrogen receptor (ER) α and β expression were assessed in paraffin sections. Student’s t tests for equality of means were used to assess differences between exposed and unexposed groups. The density of mammary buds was significantly increased in BPA-exposed monkeys, and the overall development of their mammary gland was more advanced compared with unexposed monkeys. No significant differences were observed in ER expression. Altogether, gestational exposure to the estrogen-mimic BPA altered the developing mammary glands of female nonhuman primates in a comparable manner to that observed in rodents.

Barriers to Cancer Development

10th Thursday, 2012  |   Others  |  no comments

Cancer is a disease of the old. Before cancer becomes symptomatic, it is believed that there usually exist a long latency period, often about 20-30 years. In other words, the initial trigger that induces cancer development occurs many years before the actual development of cancer. It is well known that the treatment of cancer is an uphill task. Many major pharmaceutical companies are spending huge amounts of money, yet the development of a successful anti-cancer drug is very rare. So there is something that we must think about. If cancer develops years after the initial trigger, then we would in theory have a long period within which we can try to catch the signs of future cancer development while the patients are still healthy. Developing methods to detect early stages of cancer and to be able to halt further progression of the cancer before overt cancer develops would be perhaps ideal ways to control cancer. Therefore, it is important to study early stage of cancer development.

We have been studying the gene called RUNX3 and its involvement in human cancer for some time. As will be discussed below, RUNX3 might be one of the genes that may contribute to early diagnosis.
RUNX gene is a mammalian homolog of Drosophila segmentation gene, Runt. The cDNA sequence of Runt was described first by Peter Gergen. Then Misao Ohki identified AML1 gene on chromosome 21 that is involved in chromosomal translocation, t(8;21), which is the most frequently observed chromosome translocation in acute myeloid leukemia. We were studying transcription factors that regulate gene expression of polyomavirus in developmentally regulated fashion. One of them was polyomavirus enhancer binding protein 2 (PEBP2). Nancy Speck identified a transcription factor called Core Binding Factor (CBF) that regulates retrovirus gene expression. PEBP2 and CBF turned out to be identical and they are heterodimeric transcription factors. The cDNA sequences of Runt, AML1 and DNA binding subunit of PEBP2 and CBF are highly related and we now call them as the RUNX family. From the sequence comparison, it was clear that the gene family is a developmental regulator, involved in human cancer and functions as a transcription factor (Figure1). There are three mammalian RUNX genes, called RUNX1, RUNX2 and RUNX3. These genes are evolutionarily very old and regulate cell specification in development. Developmental regulation and cancer are two different sides of the same coin. We are interested in studying these genes, since our primary interest is to uncover the mechanism by which cancer develops.

We began working on RUNX3 because we found its expression in stomach and intestine and there was a hint that this gene may be involved in stomach and colorectal cancer. To study the gene function, we disrupted Runx3 gene in mouse and examined the changes in intestine and stomach. To analyze intestinal phenotype, we study our Runx3+/- mouse side by side with Min mouse. Min mouse is a mouse line in which one of the allele of APC (adenomatous polyposis coli) gene is inactivated. APC gene is a well-known colon cancer gene and most of the colon cancer patients usually have an impaired APC gene. Min mouse is a standard mouse model to study the mechanism by which APC gene induces colon cancer. In human, colon cancer is common but cancer in small intestine is rare, whereas mouse develops intestinal tumors but only rarely in colon. Tumor formation in intestine in mouse is considered to be a model of human colon cancer. Usually, the function of APC gene is studied in one of the inbred mouse strains, C57BL/6. In this strain, intestinal tumors develop in Min mouse in several months. However, in different mouse strains, the same genetic change in APC gene causes tumors to develop very slowly. The reason is that there is a gene that inhibits the tumor growth when APC gene is inactivated. C57BL/6 strain does not have the function of this gene. We studied Min mutation and Runx3 heterozygous mutation in parallel in BALB/c strain. The reason why we used BALB/c strain was because Runx3-/- mice in C57BL/6 strain die soon after birth, whereas significant percentage of BALB/c strain with Runx3-/- genotype can survive to adulthood. Ironically, Runx3-/- mice did not spontaneously develop tumors. Other investigators also observed that biallelic inactivation of well-known tumor suppressor genes some times do not induce tumors. However, we found that both Min mice and Runx3+/- mice developed several small adenomas, premalignant tumors, at around 15 months after birth: tumor morphology and incidence are remarkably similar. Genomic studies showed that adenomas that developed in Min mice showed homozygous mutation in APC gene, while Runx3 locus did not show any change. On the other hand, in adenomas developed in Runx3+/- mice, there was no sign of genetic alteration in APC gene. Instead, both alleles of Runx3 were inactivated by promoter hypermethylation. This is reminiscent of the frequent observations of RUNX3 hypermethylation in human colorectal cancer. Interestingly, analysis of very small adenomas formed in the compound mice showed either biallelic mutation of APC gene without affecting Runx3 gene or biallelic silencing of Runx3 gene without affecting APC gene. These results strongly suggest that heterozygous mutation of both APC and Runx3 genes are nearly equivalent in inducing adenomas in mouse intestine. Importantly, analysis of human sporadic adenomas revealed similar results. We found that Runx3 attenuates the oncogenic Wnt signaling pathway and that the human gastric cancer-derived mutation R122C is deficient in attenuation of Wnt signaling. These are strong evidence of tumor suppressor activity in Runx3. The results clearly indicate that APC gene and Runx3 gene are similar in inducing early stage of cancer development. APC is characterized as a “gatekeeper” of colon carcinogenesis. Runx3 also functions in the early stage of colon carcinogenesis.

We also studied the knockout phenotype in stomach. In this case, we treated mice with chemical carcinogen which is known to induce gastric cancer. When we give mice N-methyl-N- nitrosourea (MNU) for 10 weeks from 8 weeks of age in drinking water, wild type mice will develop cancer in 1 year of age. We used a smaller dose which will not cause tumor development in wild type mice. When Runx3-/- mice were treated similarly, 100% of the mice developed adenocarcinoma. Runx3+/- mice showed intermediate value, namely showing adenoma and dysplasia. These results show that absence of Runx3 makes mice prone to induce gastric cancer.

From the study of intestine and stomach, we found that Runx3 functions at the beginning of cancer development. This notion is consistent with the results obtained from different studies by others. It has been shown that all Runx1, Runx2 and Runx3 genes induce cellular senescence, that is, permanent cessation of cell division. When activation of oncogene, such as Ras oncogene occurs in normal cells, the cell growth would be strongly stimulated. When this happens in normal cells, however, cellular fail-safe mechanism is activated to stop abnormal cell growth, since such aberrant growth of cells would be harmful to a healthy body. Therefore, Runx genes are at least a part of the fail-safe machinery in our body. If Runx genes are inactivated, the cell would lose a fail-safe mechanism and cells in which oncogenic Ras is activated would keep growing. This is the basis of the first step of carcinogenesis. When these cells acquire additional genetic changes, the cells would gradually become cancer.

It has been known that DNA damage response is a barrier for cancer development. That is to say that when DNA, which stores hereditary information and gets transmitted from generation to generation, is damaged by radiation or toxic substance, our body is equipped with multiple levels of repair mechanisms to rectify such damages. It is now known that the DNA damage response is also activated as an anti-cancer barrier in response to oncogenes such as Ras. This is because oncogenes can also induce DNA damage by increasing the rate of DNA replication. Thus, if this system becomes defective, then damaged DNA would remain in the body which would gradually cause the genomic instability. When genomic instability persists, activation of oncogene or inactivation of tumor suppressor genes could be generated to eventually induce cancer. Therefore, DNA damage response is considered to be an essential barrier to prevent carcinogenesis from being initiated. We found that Runx3 is also involved in DNA damage response.

All these evidence support the notion that Runx3 functions at the initial stage of cancer development. Obviously, cells in our body are protected by multi-levels of protective mechanisms. RUNX family genes seem to be a part of this protective machinery to play a role as a barrier to protect normal cells from becoming malignant. We believe this is the basis of the tumor suppressor activity of RUNX3.

Our studies revealed that RUNX3 is one of the genes that will be worthwhile to study for the purpose of identifying clues of very early stage of cancer. One of the points to note is that mutations in RUNX3 gene in various cancers are rare. RUNX3 is frequently inactivated by methylation of the promoter region. Promoter methylation is the structural modification of the DNA in the regulatory region of the gene to control the expression of the gene. Many tumor suppressor genes are known to be inactivated by promoter methylation. When this structural modification occurs, gene expression is silenced. This is functionally equivalent to mutation of the gene to inactivate it. Interestingly, there have been reports that RUNX3 methylation is a good diagnostic tool for a certain type of colon cancer. Technology to detect methylation of genes is improving. Since RUNX3 is a transcription factor which activates or represses target genes, there is a possibility to detect one of the target genes as a surrogate marker for inactivation of RUNX3. Some of them could be useful tool to detect RUNX3 inactivation.

Granted, it is the job of Opposition parties to oppose the

10th Thursday, 2012  |   Uncategorized  |  no comments

They have relied more on contractor word of mouth, but lots of LP radio ads have helped their branding lately. They are also the corporate sponsor of LP field, where the Tennessee Titans play. Their corporate headquarters are in Nashville, and they do have a Minnesota plant up in Two Harbors.

Red Bottoms Sneakers Opposition parties recently accused our government of softening its opposition to American country of origin labelling (COOL) rules on food imports. The trouble is, they based their assumption on information that had changed completely after the new American administration took office this year. Granted, it is the job of Opposition parties to oppose the government.. Red Bottoms Sneakers

Christian Louboutin You will not be disappointed.No matter your style, size or budget, you will find something there. The trick is to know how to look. Here I give you my five tips to shop UAL like a pro.1. During the investigation it was evident that the student in the costume was surprised to learn that this post had been made. He was shocked that some people thought that he was complicit in staging the photo. We believe that based on what we have learned, he was unaware of the post being made and specifically did not know about the girl comments until we addressed it with him. Christian Louboutin

Cheap Christian Louboutin Shoes The lady in red, as we all know, is anything but a lady. She’s a seductress, a sex bomb Louboutin Shoes Sale, a temptress. After all, if a woman wants to appear blushing, coy or virginal, she never reaches for the little red dress in the back of her wardrobe. Let compare the just opened Porch to its impressive established near neighbour, St Heliers Bay Bistro. Hip Group, owners of St Heliers Bay Bistro and other excellent waterside cafes at Kohimarama and Takapuna Louboutin Shoes Sale, have long been the arbiters of good in the city once appallingly moribund waterfront brunching experience. Is it a wise idea for a new establishment to attempt to take on such a strong competitor Red Bottoms Sneakers, just a few doors away? Porch has an immediate disadvantage in its building design, which, unlike the brilliant https://www.redbottomshoes.co.uk, sunny, inside outness of its near competitor, offers two distinct dining experiences the haves, at the strip of tables outside in the bright summer light Red Bottom Shoes, and the have nots, inside in the air conditioned half light. Cheap Christian Louboutin Shoes

UK Christian Louboutin And the ‘Ooops not anymore’ comment is pretty childish too. Especially when there’s people reading this who’ve devoted lots of time and effort to see her fly again despite all the odds being against it. Morons. Huh, File). FILE In this Aug. 17, 2016, file photo, Chicago Cubs’ Jorge Soler watches his three run home run during the first inning of a baseball game against the Milwaukee Brewers in Chicago UK Christian Louboutin.