Steroid hormones, particularly androgens, play a major role in prostatic carcinogenesis. Personal history of severe acne, a surrogate for higher androgen activity, has been associated with an increased risk of prostate cancer (PCa), and one recent study indicated that severe teenage acne was a novel risk factor for melanoma. These findings suggest a possible relationship between PCa and risk of melanoma. We prospectively evaluated this association among US men.
A total of 42,372 participants in the Health Professionals' Follow-Up Study (HPFS; 1986 to 2010) were included. Biennially self-reported PCa diagnosis was confirmed using pathology reports. Diagnosis of melanoma and nonmelanoma skin cancer (NMSC) was self-reported biennially, and diagnosis of melanoma was pathologically confirmed. We sought to confirm the association in 18,603 participants from the Physicians' Health Study (PHS; 1982 to 1998).
We identified 539 melanomas in the HPFS. Personal history of PCa was associated with an increased risk of melanoma (multivariate-adjusted hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54). Although we also detected a marginally increased risk of NMSC associated with PCa (HR, 1.08; 95% CI, 0.995 to 1.16), the difference in the magnitude of the association between melanoma and NMSC was significant (P for heterogeneity = .002). We did not find an altered risk of melanoma associated with personal history of other cancers. The association between PCa and risk of incident melanoma was confirmed in the PHS (HR, 2.17; 95% CI, 1.12 to 4.21).
Personal history of PCa is associated with an increased risk of melanoma, which may not be entirely a result of greater medical scrutiny.
The role of diet in hepatocellular carcinoma (HCC) and its typical precursor, chronic liver disease (CLD), is poorly understood. Following dietary recommendations has been shown to reduce risk of many cancers, but whether such diets are associated with HCC and CLD is unknown. We prospectively evaluated the association of two dietary indices, the Healthy Eating Index-2010 (HEI-2010) and the alternate Mediterranean Diet Score (aMED), with HCC incidence and CLD mortality in a large U.S. prospective cohort. We calculated the HEI-2010 and aMED scores for 494,942 participants in the National Institutes of Health-AARP Diet and Health study, based on typical diet assessed using a food frequency questionnaire between 1995 and 1996. Hazard ratios (HRs) and 95% confidence intervals (CIs) for quintiles of each index were estimated using Cox proportional hazards regression, after adjusting for alcohol intake, smoking, body mass index, diabetes, and other covariates. A total of 509 HCC cases (1995-2006) and 1053 CLD deaths (1995-2011) were documented during follow-up. Higher HEI-2010 scores, reflecting favorable adherence to dietary guidelines, were associated with lower risk of HCC (HR: 0.72, 95% CI: 0.53-0.97 for the highest quintile compared to lowest; P-trend=0.03), and lower mortality due to CLD (HR: 0.57; 95% CI: 0.46-0.71; P-trend<0.0001). High aMED scores were also associated with lower risk of HCC (HR: 0.62; 95% CI: 0.47-0.84; P-trend=0.0002) and lower risk of CLD mortality (HR: 0.52; 95% CI: (0.42-0.65; P-trend<0.0001). Conclusions: Adhering to dietary recommendations may reduce the risk of developing HCC and dying of CLD.
diet; liver cancer; Healthy Eating Index-2010; alternate Mediterranean Diet Score; cohort study
Background & Aims
Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers.
We analyzed data from 494,968 participants in the National Institutes of Health (NIH)-AARP Diet and Health study, in which AARP members (51–70 y old) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index.
During the follow-up period (1995–2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest: hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.31–0.86; Ptrend=.001) and EAC (HR, 0.75; 95% CI, 0.57–0.98; Ptrend=.01). We observed an inverse association between ESCC, but not EAC, and higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not significantly associated with gastric cardia or noncardia adenocarcinomas.
Using data collected from 1995 through 2006 from the NIH-AARP Diet and Health Study, HEI-2005 and aMED scores were inversely associated with risk for esophageal cancers—particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers.
food habits; esophageal neoplasms; stomach neoplasms
Germline genetic variants in PLCE1 (10q23) have demonstrated consistent associations with risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer among Chinese. We evaluated PLCE1 mRNA and protein expression in paired tumor-normal tissues, and their relationship with survival.
PLCE1 mRNA was profiled using three probes in the Affymetrix GeneChip U133 for paired tumor-normal tissues of ESCC (n=132), gastric cardia adenocarcinoma (GCA, n=62) and gastric noncardia adenocarcinoma (GNCA, n=72). We used immunohistochemistry to detect PLCE1 protein on slides from tissue microarrays in paired tumor-normal tissues of ESCC (n=303), and tumors of GCA (n=298) and GNCA (n=124).
Compared with normal tissues, PLCE1 mRNA expression was significantly reduced in ESCC tumors (P=0.03, probe_205112_at), as well as in GCA and GNCA tumors (P<0.0001, each probe). Protein expression was non-significantly reduced in ESCC tumors (P=0.51). Increased tumor-normal mRNA fold change (probe_205112_at) was associated with longer survival in ESCC (9.6 months for highest vs lowest quartile; P-trend=0.02). Increased mRNA tumor-normal fold change (probe_205111_at) was associated with longer survival for GCA (10.7 months for highest quartile; P-trend=0.04), but not for GNCA cases (P=0.72). Similar to mRNA, elevated tumor-normal fold change for protein in ESCC was also associated with improved survival (8.1 months for highest quartile; P-trend=0.04).
Dysregulated PLCE1 mRNA expression was observed for both ESCC (one probe only) and GCA tumors, and the altered PLCE1 expression appears to be associated with cancer prognosis.
A potential role for PLCE1 in the early detection and/or therapy of ESCC and GCA warrants further investigation.
Among 2258 Helicobacter pylori–seropositive subjects randomly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo, we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age, baseline gastric histopathology, and post-treatment infection status. We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses, respectively. Treatment was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36; 95% confidence interval [CI] = 0.17 to 0.79) and mortality (hazard ratio = 0.26; 95% CI = 0.09 to 0.79) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56; 95% CI = 0.34 to 0.91). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology, and benefits are present even with post-treatment infection, suggesting treatment can benefit an entire population, not just the young or those with mild histopathology.
Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma.
Based on the Nurses’ Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports and tumor blocks were collected by mail from across the United States. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene Set Enrichment Analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes.
The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases.
We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.
melanoma; genetic pathway analysis; genome-wide expression profiling
Previous studies suggest that solar UV exposure in early life is predictive of cutaneous melanoma risk in adulthood, whereas the relation of BRAF mutation with sun exposure and disease prognosis has been less certain. We investigated the associations between BRAFV600E and NRASQ61R mutations and known risk factors, clinicopathologic characteristics and clinical outcomes of melanoma in a case series of primary invasive cutaneous melanoma from the Nurses' Health Study (NHS).
Somatic BRAFV600E and NRASQ61R mutations of 127 primary invasive melanomas from the NHS cohort were determined by pyrosequencing using formalin-fixed, paraffin-embedded block tissues. Logistic regression analyses were performed to detect the associations of mutations with melanoma risk factors, and Kaplan-Meier method was used to examine associations between mutations and survival.
The odds ratios for harboring BRAFV600E mutations was 5.54 (95% CI, 1.19-25.8, Ptrend=0.02) for women residing in states with UV index ≥7 versus those residing in states with UV index ≤5 at 30 years of age. Patients with BRAFV600E mutations tended to have shorter melanoma-specific survival when compared to patients wild-type at both loci (median survival time 110 months vs. 159 months) (P=0.03).
BRAF V600E mutations in primary cutaneous melanomas were associated with residence in locations with medium and high UV indices in mid life. BRAFV600E mutation may be associated with an unfavorable prognosis among melanoma patients.
BRAF; melanoma; NRAS; sun exposure; survival
Individuals with psoriasis are shown to have an elevated risk of hypertension, and anti-hypertensive medications, especially beta-blockers, have been linked to psoriasis development. However, the association of prior existing hypertension and anti-hypertensive medications with risk of incident psoriasis has not been accessed using prospective data.
To evaluate the association of hypertension and anti-hypertensive medications with risk of psoriasis based on data from the Nurses’ Health Study (NHS).
Prospective cohort study (1996–2008).
Nurses’ Health Study.
A total of 77,728 U.S. women who provided biennially updated data on hypertension and anti-hypertensive medications.
Main Outcome and Measure
We documented a total of 843 incident psoriasis cases during 1,066,339 person-years of follow-up. Compared to normotensive women, women with hypertension duration more than 6 years were at a higher risk of developing psoriasis [HR=1.27, 95% confidence interval (CI), 1.03–1.57]. In stratified analysis, the risk of psoriasis was higher among hypertensive women without medication [HR=1.49, 95% CI, 1.15–1.92] and among hypertensive women with current medication [HR=1.31, 95% CI, 1.10–1.55] when compared to normotensive participants without medication. Compared to women who never used beta-blockers, the multivariate HRs for psoriasis were 1.11 (95% CI, 0.82–1.51) for women who regularly used 1–2 years, 1.06 (95% CI, 0.79–1.40) for 3–5 years, and 1.39 (95% CI, 1.11–1.73) for 6 or more years (P for trend=0.009). There was no association between other individual anti-hypertensive drugs and risk of psoriasis.
Long-term hypertensive status is associated with an increased risk of psoriasis. Long-term regular use of beta-blockers may also increase the risk of psoriasis.
The RAS/RAF/MEK/ERK signaling pathway plays a crucial role in melanoma cell proliferation and survival. Sildenafil (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk.
To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States.
Design, Setting and Participants Design
In 2000, participants in the Health Professionals’ Follow-up Study (HPFS), an ongoing prospective study. were inquired regarding sildenafil use for erectile dysfunction. We excluded baseline cancers, type 2 diabetes, coronary heart disease, stroke, and hypertension. A total of 14,912 men were included.
Main Outcome Measure
Incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed.
We identified 79 melanoma, 305 SCC, and 1,720 BCC cases during the follow-up (2000–2010). Sildenafil use was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 2.24 (95% confidence interval (CI): 1.05–4.78). In contrast, we did not observe an increase in risk of SCC (HR = 0.80, 95% CI: 0.46–1.37), or BCC (HR = 1.05, 95% CI: 0.84–1.30) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma.
Sildenafil use may be associated with an increased risk of developing melanoma.
Sildenafil; melanoma; prospective study
There is a paucity of data on basal-cell carcinoma (BCC) in the United States, since most national registries do not collect information on BCC. We evaluated BCC incidence trends and associated risk factors for BCC in 140,171 participants from a US female cohort, the Nurses' Health Study (1986–2006), and a US male cohort, the Health Professionals' Follow-up Study (1988–2006). Age-adjusted BCC incidence rates increased from 519 cases per 100,000 person-years to 1,019 cases per 100,000 person years for women and increased from 606 cases per 100,000 person-years to 1,488 cases per 100,000 person-years for men during the follow-up period. Cox proportional hazards analysis identified the following phenotypic risk factors for BCC in both cohorts: family history of melanoma, blond or red hair colors, higher number of extremity moles, higher susceptibility to sunburn as a child/adolescent, and higher lifetime number of severe/blistering sunburns. The multivariate-adjusted risk ratio for the highest quintile of cumulative midrange ultraviolet B flux exposure versus the lowest quintile was 3.18 (95% confidence interval: 2.70, 3.76) in women and 1.90 (95% confidence interval: 1.57, 2.29) in men. BCC incidence was generally higher in men than in women, and BCC risk was strongly associated with several phenotypic and exposure factors, including midrange ultraviolet B radiation, in our study populations.
basal-cell carcinoma; incidence; skin cancer; ultraviolet radiation
Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
Psoriasis is a systemic inflammatory disorder associated with an increased risk of cardiovascular disease. Hypercholesterolemia is a major risk factor for cardiovascular disease, and patients with psoriasis or psoriatic arthritis (PsA) have been shown to have elevated cholesterol levels. However, whether hypercholesterolemia is associated with an increased risk of psoriasis or PsA is unknown. We aim to evaluate whether a history of hypercholesterolemia is associated with the risk of developing psoriasis and PsA in a cohort of US women.
A total of 95,540 participants were included from the Nurses' Health Study II (1991–2005). Information on personal history of physician-diagnosed hypercholesterolemia and related medication use was collected during the follow-up. Clinician-diagnosed psoriasis and PsA was ascertained and confirmed by supplementary questionnaires.
During 1,320,765 person-years of follow-up, we documented 646 incident psoriasis and 165 concomitant PsA cases. Hypercholesterolemia was associated with an elevated risk of incident psoriasis [Hazard ratio (HR)=1.25, 95% confidence interval (CI): 1.04, 1.50] and PsA (HR=1.58, 95% CI: 1.13, 2.23) in multivariate adjusted models. Participants with hypercholesterolemia duration time ≥ 7 years were at a higher risk of developing psoriasis (HR=1.29, 95% CI: 1.03, 1.61) (Ptrend=0.0002) and PsA (HR=1.68, 95% CI: 1.12, 2.52) (Ptrend=0.002). These associations persisted among participants who never took cholesterol-lowering medications. There was no association between cholesterol-lowering drugs and risk of psoriasis or PsA.
Our study provides evidence that hypercholesterolemia, a well-known cardiovascular risk factor, is also associated with an elevated risk of psoriasis and PsA.
hypercholesterolemia; inflammation; psoriasis; psoriatic arthritis
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10−
4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10−
6) and in GC was CLK2 (P = 3.02 × 10−
4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), shares clinical and immunological features with psoriasis. Genome-wide association studies have found common susceptibility genes. However, epidemiologic data evaluating the association between psoriasis, psoriatic arthritis and risk of IBD are sparse. We aimed to evaluate the association between psoriasis, psoriatic arthritis and incident CD and UC among women in the USA.
174 476 women were enrolled in the Nurses’ Health Study (NHS) (1996–2008) and NHS II (1991–2007). Lifetime history of physician-diagnosed psoriasis and psoriatic arthritis was confirmed by supplementary questionnaires. Information on CD and UC was obtained by self-reported questionnaires and confirmed by medical record review.
We documented 188 incident cases of CD and 240 incident cases of UC during follow-up. Psoriasis was associated with a significantly increased risk of subsequent CD with a multivariate-adjusted relative risk (RR) of 4.00 (95% CI 1.72 to 9.27) for NHS and 3.76 (1.82 to 7.74) for NHS II. By contrast, we did not observe a significant increase in risk of UC associated with psoriasis. In a pooled analysis of both cohorts, women with psoriasis experienced a significantly increased risk of CD (RR, 3.86, 95% CI 2.23 to 6.67), but not UC (RR, 1.17, 95% CI 0.41 to 3.36). The risk of CD was especially pronounced among psoriatics with concomitant psoriatic arthritis (RR, 6.43, 95% CI 2.04 to 20.32).
Psoriasis with concomitant psoriatic arthritis is associated with an increased risk of incident CD.
No studies on the risk factors of 2009 pandemic influenza A (H1N1) in China have been reported. We aimed to investigate the risk factors for severe manifestations of 2009 pandemic H1N1 influenza in China
A case–control study with 343 severe hospitalized patients and 343 randomly selected mild controls was conducted. The diagnosis was established by assessment of clinical symptoms and confirmed by the real-time reverse-transcriptase-polymerase chain reaction assay. Severe or mild patients were classified by uniform criteria issued by the Ministry of Health in China.
The multivariable logistic regression analysis showed that the overweight or obese subjects admitted to hospital with H1N1 influenza were more likely to experience severe manifestations. The ORs were 3.70 (95% CI: 2.04-6.72) and 35.61 (95% CI: 7.96-159.21) respectively. Subjects at age less than 5 years or older than 60 years had an increased risk of severe manifestations (OR = 21.14, 95% CI: 7.79-57.33). We also observed increased risk among subjects with longer time interval from symptom onset to hospital admission (OR = 3.26, 95% CI: 2.08-5.11) or peasants (OR = 9.79, 95% CI: 5.11-18.78). Those with chronic disorders had increased risk of severe manifestations of H1N1 influenza.
We provide evidence on the risk factors associated with severe manifestations of 2009 pandemic H1N1 influenza in a study of hospitalized subjects in China.
Severe manifestation; Novel influenza A; Risk factor
Nowadays, ion implantation is an extensively used technique for material modification. Using this method, we can tailor the properties of target materials, including morphological, mechanical, electronic, and optical properties. All of these modifications impel nanomaterials to be a more useful application to fabricate more high-performance nanomaterial-based devices. Ion implantation is an accurate and controlled doping method for one-dimensional nanomaterials. In this article, we review recent research on ion implantation-induced effects in one-dimensional nanostructure, such as nanowires, nanotubes, and nanobelts. In addition, the optical property of single cadmium sulfide nanobelt implanted by N+ ions has been researched.
Nanomaterials; Ion implantation; Doping
AU-rich elements (AREs), residing in the 3′ untranslated region (UTR) of many labile mRNAs, are important cis-acting elements that modulate the stability of these mRNAs by collaborating with trans-acting factors such as tristetraprolin (TTP). AREs also regulate translation, but the underlying mechanism is not fully understood. Here we examined the function and mechanism of TTP in ARE-mRNA translation. Through a luciferase-based reporter system, we used knockdown, overexpression, and tethering assays in 293T cells to demonstrate that TTP represses ARE reporter mRNA translation. Polyribosome fractionation experiments showed that TTP shifts target mRNAs to lighter fractions. In murine RAW264.7 macrophages, knocking down TTP produces significantly more tumor necrosis factor alpha (TNF-α) than the control, while the corresponding mRNA level has a marginal change. Furthermore, knockdown of TTP increases the rate of biosynthesis of TNF-α, suggesting that TTP can exert effects at translational levels. Finally, we demonstrate that the general translational repressor RCK may cooperate with TTP to regulate ARE-mRNA translation. Collectively, our studies reveal a novel function of TTP in repressing ARE-mRNA translation and that RCK is a functional partner of TTP in promoting TTP-mediated translational repression.
Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.
Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein ) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging.
Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7–dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7–deficient hosts underwent G1 arrest, whereas 27Kip1-deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conventional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation.
Lymphocytes are the central mediators of the immune response, requiring cytokines for survival and proliferation. Survival signaling targets the Bcl-2 family of apoptotic mediators, however, the pathway for the cytokine-driven proliferation of lymphocytes is poorly understood. Here we show that cytokine-induced cell cycle progression is not solely dependent on the synthesis of cyclin-dependent kinases (Cdks) or cyclins. Rather, we observe that in lymphocyte cell lines dependent on interleukin-3 or interleukin-7, or primary lymphocytes dependent on interleukin 7, the phosphatase Cdc25A is the critical mediator of proliferation. Withdrawal of IL-7 or IL-3 from dependent lymphocytes activates the stress kinase, p38 MAPK, which phosphorylates Cdc25A, inducing its degradation. As a result, Cdk/cyclin complexes remain phosphorylated and inactive and cells arrest before the induction of apoptosis. Inhibiting p38 MAPK or expressing a mutant Cdc25A, in which the two p38 MAPK target sites, S75 and S123, are altered, renders cells resistant to cytokine withdrawal, restoring the activity of Cdk/cyclin complexes and driving the cell cycle independent of a growth stimulus.
Interleukin-1 (IL-1), IL-17 and tumor necrosis factor alpha (TNF-α) are the main proinflammatory cytokines implicated in cartilage breakdown by matrix metalloproteinase (MMPs) in arthritic joints. We studied the impact of an anti-neoplastic antibiotic, mithramycin, on the induction of MMPs in chondrocytes. MMP-3 and MMP-13 gene expression induced by IL-1β, TNF-α and IL-17 was downregulated by mithramycin in human chondrosarcoma SW1353 cells and in primary human and bovine femoral head chondrocytes. Constitutive and IL-1-stimulated MMP-13 levels in bovine and human cartilage explants were also suppressed. Mithramycin did not significantly affect the phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase. Despite effective inhibition of MMP expression by mithramycin and its potential to reduce cartilage degeneration, the agent might work through multiple unidentified mechanisms.
The antiapoptotic function of the interleukin-7 (IL-7) receptor is related to regulation of three members of the Bcl2 family: synthesis of Bcl2, phosphorylation of Bad, and cytosolic retention of Bax. Here we show that, in an IL-7-dependent murine T-cell line, different regions of the IL-7 receptor initiate the signal transduction pathways that regulate these proteins. Both Box1 and Y449 are required to signal Bcl2 synthesis and Bax cytosolic retention. This suggests a sequential model in which Jak1, which binds to Box1, is first activated and then phosphorylates Y449, leading to Bcl2 and Bax regulation, accounting for approximately 90% of the survival function. Phosphorylation of Bad required Box1 but not Y449, suggesting that Jak1 also initiates an additional signaling cascade that accounts for approximately 10% of the survival function. Stat5 was activated from the Y449 site but only partially accounted for the survival signal. Proliferation required both Y449 and Box1. Thymocyte development in vivo showed that deletion of Y449 eliminated 90% of αβ T-cell development and completely eliminated γδ T-cell development, whereas deleting Box 1 completely eliminated both αβ and γδ T-cell development. Thus the IL-7 receptor controls at least two distinct pathways, in addition to Stat5, that are required for cell survival.