Prostate cancer (PCa) is the second leading cause of cancer deaths in men. A better understanding of the molecular basis of prostate cancer proliferation and metastasis should enable development of more effective treatments. In this study we focused on the lncRNA, prostate cancer associated transcript 29 (PCAT29), a putative tumor suppressive gene. Our data show that the expression of PCAT29 was reduced in prostate cancer tumors compared to paired perinormal prostate tissues. We also observed substantially lower levels of PCAT29 in DU145 and LNCaP cells compared to normal prostate (RWPE-1) cells. IL-6, a cytokine which is elevated in prostate tumors, reduced the expression of PCAT29 in both DU145 and LNCaP cells by activating signal transducer and activator of transcription 3 (STAT3). One downstream target of STAT3 is microRNA (miR)-21, inhibition of which enhanced basal PCAT29 expression. In addition, we show that resveratrol is a potent stimulator of PCAT29 expression under basal condition and reversed the down regulation of this lncRNA by IL-6. Furthermore, we show that knock down of PCAT29 expression by siRNA in DU145 and LNCaP cells increased cell viability while increasing PCAT29 expression with resveratrol decreased cell viability. Immunohistochemistry studies showed increased levels of STAT3 and IL-6, but low levels of programmed cell death protein 4 (PDCD4), in prostate tumor epithelial cells compared to adjacent perinormal prostate epithelial cells. These data show that the IL-6/STAT3/miR-21 pathway mediates tonic suppression of PCAT29 expression and function. Inhibition of this signaling pathway by resveratrol induces PCAT29 expression and tumor suppressor function.
Cisplatin is chemotherapy used for solid tumor treatment like lung, bladder, head and neck, ovarian and testicular cancers. However, cisplatin-induced ototoxicity limits the utility of this agent in cancer patients, especially when dose escalations are needed. Ototoxicity is associated with cochlear cell death through DNA damage, the generation of reactive oxygen species (ROS) and the consequent activation of caspase, glutamate excitotoxicity, inflammation, apoptosis and/or necrosis. Previous studies have demonstrated a role of CXC chemokines in cisplatin ototoxicity. In this study, we investigated the role of CXCL1, a cytokine which increased in the serum and cochlea by 24 h following cisplatin administration. Adult male Wistar rats treated with cisplatin demonstrated significant hearing loss, assessed by auditory brainstem responses (ABRs), hair cell loss and loss of ribbon synapse. Immunohistochemical studies evaluated the levels of CXCL1 along with increased presence of CD68 and CD45-positive immune cells in cochlea. Increases in CXCL1 was time-dependent in the spiral ganglion neurons and organ of Corti and was associated with progressive increases in CD45, CD68 and IBA1-positive immune cells. Trans-tympanic administration of SB225002, a chemical inhibitor of CXCR2 (receptor target for CXCL1) reduced immune cell migration, protected against cisplatin-induced hearing loss and preserved hair cell integrity. We show that SB225002 reduced the expression of CXCL1, NOX3, iNOS, TNF-α, IL-6 and COX-2. Similarly, knockdown of CXCR2 by trans-tympanic administration of CXCR2 siRNA protected against hearing loss and loss of outer hair cells and reduced ribbon synapses. In addition, SB225002 reduced the expression of inflammatory mediators induced by cisplatin. These results implicate the CXCL1 chemokine as an early player in cisplatin ototoxicity, possibly by initiating the immune cascade, and indicate that CXCR2 is a relevant target for treating cisplatin ototoxicity.
Background: Lovastatin is one of FDA-approved drugs used to treat hypercholesterolemia to reduce cardiovascular diseases. It is a compound of the statin family derived from type of species of Aspergillus terruses. Lovastatin targets hepatocytes and blocks the cholesterol synthesis pathway by inhibiting the rate-limiting enzyme 3-hydroxy-3-methyl glutaryl CoA reductase (HMG-CoA reductase). This leads to decreased production of cholesterol and many other biochemical end products, including ubiquinone and dolichol. These biochemical end products are important for cancer progression. When lovastatin blocks their production, it leads to increased apoptosis of cancer cells. Therefore, lovastatin has promising anticancer activities but the detailed mechanisms remain poorly understood. Long noncoding RNAs are originally thought as nonfunctional. Emerging evidence suggest that lncRNAs have crucial roles in many biologic functions like apoptosis and cell cycle, translation control, epigenetic regulation and splicing regulation. In this study, we set out to identify and determine Lnc-RNAs that can regulate tumor cell responses towards lovastatin treatment. Methods: PC3, Heya8, HCT116 cells were obtained from ATCC. HCT116 p53-/- cells were gifts from Dr. Yin-Yuan Mo. The cytotoxic effects of lovastatin on those cell lines were evaluated by several approaches like MTS assays and morphologic changes. The qPCR array was used to identify lncRNAs whose levels are changed by lovastatin treatment. The regulation of lncRNA by lovastatin was further confirmed in multiple cell lines. Results and Conclusion: Lovastatin treatment had cytotoxic effects in multiple cell lines we evaluated. Through profiling array, we have identified NEAT1, MALAT1, and RMST as a responder to lovastatin. The lncRNAs identified had a significant increase in the expression compared to the nontreated cells in a dose- and time-dependent manner. The RMST mRNA expression in the HCT116 p53-/- cell line was about 25-fold more than its level in the HCT116 wild-type cells after treatment of 20 μM lovastatin for 48 hours, suggesting a role of tumor suppressor p53 gene in regulating the RMST expression. We knocked out RMST using CRISPR-Cas9 approach and found that RMST is an important mediator for lovastatin to downregulate mTOR activities and reduce colony formation. Taken together, our data suggest that lncRNAs can be stimulated by lovastatin to elicit cellular responses. Citation Format: Entkhab M. Alanisi, Jiuhui Wang, Yande Guo, Daotai Nie. Long noncoding RNAs in tumor responses toward lovastatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2463.
Rustumihia is one of the biggest WWTP (Waste Water Treatment Plant) based in Baghdad the capital of Iraq. The effluent treated wastewater, were used for irrigation by the farmers nearby the Rustumihia WWTP. The growth of Iraqi population and limited development in the infrastructure to the treatment plants in Iraq like old Rustumihia project. There is a need to assess the treated effluents water that is used for irrigation. Wastewater considered as a key alternative water resource as it can be used in agriculture field to reimburse shortages in water need. In developed countries like Iraq, the irrigation by using wastewater has a long history. Continues lagging in WWTP maintenance and its infrastructure could cause many problems for the treated effluent that has its own effect on health and environment aspects. Therefore, by applying a strong management practices, for example advanced and appropriate treated and irrigated knowledge, can be used later to gain significant advantages in the same time minimizing health risks. This article discussed the treated wastewater used by farmers nearby Rustumihia treatment plant and focus on the challenges linked with wastewater irrigation.
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