Prognostic significance of microRNA 17-92 cluster expression in Egyptian chronic lymphocytic leukemia patients.

BACKGROUND: Abnormal expression patterns of microRNAs (miRs) play an important role in the development and progression of malignancy. Identification of the clinical significance and prognostic value of these small molecules in chronic lymphocytic leukemia (CLL); a disease of heterogeneous biological landscape and clinical course, has always been of tremendous translational value. AIM: To evaluate the prognostic value of microRNA17-92 cluster members in Egyptian CLL patients. METHODS: The expression levels of miR17-92 cluster members were evaluated by qRT-PCR, including miR17, miR18a, miR19a, miR19b-1, miR20a, and miR92a-1. Other investigations included serum LDH, serum ß2 microglobulin (ß2M), CD38 and ZAP70 expression by flow cytometry, fluorescence in situ hybridization (FISH) for 17p deletion, and imaging studies (computerized tomography (CT) scans of neck, chest, abdomen, and pelvis or PET-CT scans). RESULTS: Overexpression of all members of the miRNA17-92 cluster was detected in CLL patients compared to controls (p = < 0.001 for all miRs while p = 0.01 for miR19b-1). A significant positive correlation between Hb and miR17 and a significant negative correlation between Hb and miR19b-1 were observed (p = 0.041, 0.017 respectively). A statistically significant positive correlation between miR19b-1 expression and each of the WBCs and absolute lymphocytic count (ALC) was detected (p = 0.023, 0.022 respectively). Moreover, a statistically significant relation between miR19b-1 expression and advanced Binet stages was also found (p = 0.05). Regarding miR18a, a statistically significant positive correlation with LDH level was found (p = 0.003). We also found a significant positive correlation between miR92a-1 and ß2M level (p = 0.005), as well as a significant relation between miR17 and negative CD38 expression (p = 0.034). However, no significant relationships between any of studied miRNA expression levels and 17p deletion or response to treatment were observed. Patients who expressed miR19b-1 were significantly indicated to start therapy at diagnosis (p = 0.05). The overall survival of CLL patients included in our study was 90.2% after 1 year from the time of diagnosis. Patients with high expression of miR19a had better OS than those with low expression (p = 0.04). CONCLUSIONS: Overexpression of all members of the miR17-92 cluster was detected in Egyptian CLL patients. MiR18a, miR19b-1, and miR92a-1 also have an adverse prognostic value while miR17 can be considered a good prognostic marker. High expression of miR19a is associated with better OS.

High fat diet increases the weight of rat ventral prostate.

BACKGROUND: Understanding the mechanisms by which diet influences the prostate may eventually lead to novel approaches for preventing prostate cancer. The objective of this research is to examine the impact of dietary fat, vitamin D, and genistein on prostate weight, serum and intraprostatic androgen levels, and the expression of several androgen-response genes. METHODS: Sprague-Dawley rats were fed, beginning at 21 days of age, for 1 or 3 months of experimental diets with high saturated fat (32.2% calories from fat), low saturated fat (3.6% calories from fat), genistein plus (20 mg/kg), genistein deficient, vitamin D surplus (4,000 U/kg), or vitamin D deficient. The body weight, food intake, the weights of the ventral prostate and dorsolateral prostate, and the levels of testosterone and dihydrotestosterone (DHT) in the serum and in the prostate were determined. The expression of androgen-response genes was characterized by Northern blot analysis. RESULTS: The pilot experiments showed that high dietary fat appeared to consistently increase the weight of the ventral prostate, while vitamin D or genistein did not have a consistent effect on prostate weight. Further analysis confirmed that the ventral prostate is 15% (P < 0.001) heavier in the rat on a high fat diet as compared to a low fat diet. Dietary fat had no significant influence on the levels of serum and intraprostatic androgens and the expression of androgen-response genes. CONCLUSIONS: Our results suggested that the ventral prostate weight of the rat is increased without affecting the androgen axis by feeding the animals with high fat diet beginning at 21 days of age. This observation is potentially important since epidemiological data suggest that saturated fat consumption is a major risk factor associated with prostate cancer incidence rate.

Adrenomedullin gene is abundantly expressed and directly regulated by androgen in the rat ventral prostate.

A gene-expression screen, looking for androgen response genes in the rat ventral prostate, has identified adrenomedullin (AM), a 52-amino acid pluripotent peptide hormone, first isolated from pheochromocytoma. Northern blot analysis demonstrates that the level of expression in the prostate is reduced at least 25-fold by castration, with the majority of the decrease occurring in the first day, and that androgen replacement in seven-day castrated rats stimulates expression to supernormal levels, with the majority of the increase occurring within 14 h. The level of expression in the prostate is at least 50-fold higher than in the adrenal gland and cardiac atria, tissues previously reported to have the highest level of expression in the rat. In prostate organ culture, androgen was able to induce AM expression; and this induction resists protein synthesis inhibition, indicating that AM is a direct androgen response gene in the prostate. In situ hybridization of normal rat prostate tissue showed that AM expression is localized in the epithelial cells. Our analysis demonstrates that AM, a multifunctional peptide hormone, is abundantly expressed and directly regulated by androgen in the prostate epithelial cells. Thus, AM has the potential to play a crucial function in androgen action in the prostate.

Genes regulated by androgen in the rat ventral prostate.

Genes that are regulated by androgen in the prostate were studied in the rat. Four of the less than 10 genes that are down-regulated by androgen in the ventral prostate of a 7-day castrated rat were identified; their mRNAs decayed with identical kinetics. Twenty-five of the estimated 56 genes that are up-regulated by androgen in the castrated prostate have been isolated. The up-regulated genes fall into two kinetic types. Early genes are significantly up-regulated by 6.5 hr whereas the delayed genes respond mainly after 24 hr from the time of androgen replacement. These androgen-response genes are also regulated in the prostate by castration, indicating that these genes could play important roles in androgen-induced regrowth and/or castration-induced regression of the prostate during hormonal manipulation. A survey of the tissue specificity showed that the androgen-response gene expression program in the prostate is mainly prostate-specific. Total RNA Northern blot analysis detects the expression of about 16 up-regulated genes and 3 down-regulated genes in the prostate only. Four up-regulated genes and one down-regulated gene are regulated by androgen in both the prostate and seminal vesicles but not in other organs. The expression of the remaining androgen-response genes is not limited to the prostate but is only responsive to androgen in the prostate. This survey of the androgen-response gene expression program provides insights into the molecular and cellular mechanisms of androgen action in the prostate.