ABSTRACT
Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.
Subject(s)
Homeodomain Proteins/metabolism , Neoplastic Stem Cells/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Transcription Factors/metabolism , ras GTPase-Activating Proteins/metabolism , Animals , Cell Line, Tumor , GTPase-Activating Proteins/metabolism , Gene Expression Regulation, Neoplastic/physiology , Humans , Male , Mice , Mice, Knockout , Mice, SCID , Neoplasm Recurrence, Local/metabolism , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Zinc Finger E-box-Binding Homeobox 1ABSTRACT
Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.
Subject(s)
Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , ras GTPase-Activating Proteins/metabolism , Animals , Cell Line, Tumor , Disease Progression , Gene Knockdown Techniques , Humans , Male , Mice , Mice, Knockout , Prostatic Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , TransfectionABSTRACT
BACKGROUND AND PURPOSE: Urinary incontinence (UI) is a common, distressing, and often disabling condition in the elderly. The objectives of this study were to estimate the prevalence and clinical characteristics of UI among elderly individuals living at home and to explore their perceptions of UI and intention to seek medical care. METHODS: A total of 504 elderly subjects aged 65 and older residing in Tungkang town (located in the southwestern part of Taiwan) were randomly sampled and surveyed face to face by registered nurses. The prevalence, clinical types, and perceptions of UI, and intention to seek treatment, were compared with chi-square statistics across various sociodemographic characteristics. Logistic regression analyses were conducted to identify factors associated with UI experience and intention to seek treatment. RESULTS: About 22% of respondents reported that they had experienced involuntary loss of urine in daily life. Women, people who were overweight, and those who were aged 70 years or older were at higher risk of UI. While women were more likely to suffer from stress incontinence, men were at higher risk of urge incontinence. Women, illiterate individuals, and those who perceived UI as a normal part of the aging process showed low intention to seek treatment for UI. CONCLUSIONS: The results of this study suggest that public awareness programs about UI and promotion of available treatment options are necessary to increase the intention to seek treatment among the elderly. Culturally sensitive programs should be designed, particularly for female and illiterate elderly, to provide incentives to seek medical care. The increasing availability of various treatment modalities coupled with education to correct commonly held misconceptions about UI might enable more elderly individuals to receive treatment for this common condition.
Subject(s)
Patient Acceptance of Health Care , Urinary Incontinence/epidemiology , Aged , Aged, 80 and over , Female , Humans , Male , Prevalence , Urinary Incontinence/psychology , Urinary Incontinence/therapyABSTRACT
In order to assess the current seroepidemiology of hepatitis D virus (HDV) infection in Taiwan where hepatitis B virus (HBV) is hyperendemic, a total of 756 voluntary blood donors, 641 prostitutes, 1,014 patients with sexually transmitted diseases (STDs), and 628 drug abusers were studied. Radioimmunoassays were used for testing HBV infection markers and antibody against HDV (anti-HDV) among HBsAg carriers. The anti-HDV prevalence among HBsAg carriers was significantly higher in STD patients (9.6%), prostitutes (33.1%), and drug abusers (68.1%) than in blood donors from the general population (2.2%). The prevalence gradually increased with age in blood donors and STD patients, but reached a plateau at a young age in prostitutes and drug abusers. Males had a higher prevalence than females in blood donors (2.7% vs. 0), STD patients (8.2% vs. 7.5%), and drug abusers (69.0% vs. 57.1%), but the difference was not statistically significant. STD patients with syphilis had a higher prevalence (19.5%) than those affected with non-ulcerating STDs (5.3%). While unlicensed prostitutes had a lower prevalence (13.6%) than licensed prostitutes (44.9%), intravenous drug abusers had a higher prevalence (73.1%) than non-intravenous drug abusers (34.6%). There was a twofold increase in anti-HDV prevalence from 1986 to 1989 among prostitutes, but the prevalence remained unchanged in the general population and drug abusers. HDV infection remains limited to the high-risk groups and spread mainly by promiscuity and needle sharing in Taiwan.
Subject(s)
Carrier State/epidemiology , Hepatitis B Surface Antigens/blood , Hepatitis B/epidemiology , Hepatitis D/epidemiology , Adult , Carrier State/immunology , Female , Hepatitis Antibodies/blood , Hepatitis B/complications , Hepatitis B/immunology , Hepatitis D/complications , Hepatitis D/immunology , Hepatitis Delta Virus/immunology , Humans , Male , Risk Factors , Seroepidemiologic Studies , Sex Work , Sexually Transmitted Diseases/complications , Substance-Related Disorders/complications , Taiwan/epidemiologyABSTRACT
The frequencies of chromosomal aberrations (CA) and sister-chromatid exchanges (SCE) in Chinese hamster cells were significantly increased by the direct-acting mutagen N-nitroso-2-acetylaminofluorene (N-NO-AAF) at the concentration of 0.1 mM. N-NO-AAF was prepared by nitrosation of the protohepatocarcinogen 2-acetylaminofluorene. The induced CA, which included chromatid breaks, chromatid exchanges, chromosome breaks, and chromosome ring formation were significantly potentiated by the presence of sodium arsenite (10 microM), but not by hydroxyurea (20 mM) or cytosine arabinoside (25 microM). On the other hand, the clastogenic effect of N-NO-AAF was effectively inhibited by sodium selenite (100 microM). Arsenite (10 microM) was shown to be moderately active in CA induction which was partially blocked by the presence of selenite (10 nM). N-Nitroso compounds such as N-nitroso-N-methylurea, N-nitroso-N-ethylurea and N-methyl-N'-nitro-N-nitrosoguanidine were equally or more active in the induction of CA and SCE in CHO cells when compared with N-NO-AAF. The cell cycle was significantly delayed by the intervention of N-NO-AAF.
