MicroRNAs 221/222 and Genistein-Mediated Regulation of ARHI Tumor Suppressor Gene in Prostate Cancer

Chen, Yi; Zaman, Mohd Saif; Deng, Guoren; Majid, Shahana; Saini, Shranjot; Liu, Jan; Tanaka, Yuichiro; Dahiya, Rajvir

doi:10.1158/1940-6207.capr-10-0167

Cited by 140 publications

(100 citation statements)

References 23 publications

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“…Yang et al suggested that SIRT1 plays a suppressive role against the tumor promoting action of miR-221 and miR-222 (37). In addition, ADAM17, ARHI and HECTD2 were identified as the target genes of miR-221 and miR-222 (22,38,39). These findings suggest that miR-221 and miR-222 are a therapeutic target.…”

Section: Discussionmentioning

confidence: 97%

miR-222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma

Liu

Zhang

et al. 2014

International Journal of Oncology

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Abstract. The miR-222 cluster has been demonstrated to function as oncomiR in human hepatocellular carcinoma (HCC). miR-222 confers chemotherapy drug resistance in various cancers, including HCC. However, the effects and mechanisms by which miR-222 regulates liver tumorigenicity and confers sorafenib (SOR) resistance remain unclear. Here we first investigated the miR-222 effect on proliferation, cell cycle, apoptosis, migration and invasion of HCC. Our results demonstrated that miRNA inhibitors specially targeting miR-222 significantly suppressed cellular proliferation, migration, invasion and G1/S transition of the cell cycle, and induced cell apoptosis in HepG2 cells. In addition, we investigated whether miR-222 confers SOR resistance in HepG2 cells to explore it roles in acquisition of drug resistance. The results showed that miR-222 inhibitors induced sensitivity to the antitumor effect of sorafenib in human HepG2 cells. Importantly, our study also showed that miR-222 could regulate the expression of phosphorylation PI3K and AKT, which might contribute to miR-222 conferred SOR resistance in HepG2 cells. In conclusion, this study demonstrates that miR-222 can promote cell proliferation, migration and invasion, and decrease cell apoptosis, as well as enhance the resistance of HCC cells to sorafenib miR-222 through activating the PI3K/AKT signaling pathway.

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Section: Discussionmentioning

confidence: 97%

miR-222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma

Liu

Zhang

et al. 2014

International Journal of Oncology

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“…[32][33][34][35] Studies have also shown the regulatory effects of isoflavone genistein on the methylation of miR-221/222 and miR-145 in PCa cells. 36,37 These findings suggest the demethylating function of isoflavone. In our study, we found that isoflavone could demethylate the methylated promoter of miR-29a and miR-1256 and, in turn, increased the expression of miR-29a and miR-1256.…”

Section: Discussionmentioning

confidence: 81%

Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion

et al. 2012

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“…36 In addition to ovarian cancer, downregulation of ARHI has been associated with cancers at other sites, including breast, prostate, pancreatic, thyroid and lung carcinomas. 4,[37][38][39][40][41][42][43][44][45][46] Consequently, the observations made in ovarian cancer are likely to be relevant to many other types of cancer. In the future, it will be of interest to explore the interaction of ARHI and FOXo3a across cancers that originate from non-ovarian sites.…”

Section: Discussionmentioning

confidence: 99%

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

Lü¹,

Yang

Sutton

et al. 2014

Cell Death Differ

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The process of autophagy has been described in detail at the molecular level in normal cells, but less is known of its regulation in cancer cells. Aplasia Ras homolog member I (ARHI; DIRAS3) is an imprinted tumor suppressor gene that is downregulated in multiple malignancies including ovarian cancer. Re-expression of ARHI slows proliferation, inhibits motility, induces autophagy and produces tumor dormancy. Our previous studies have implicated autophagy in the survival of dormant ovarian cancer cells and have shown that ARHI is required for autophagy induced by starvation or rapamycin treatment. Re-expression of ARHI in ovarian cancer cells blocks signaling through the PI3K and Ras/MAP pathways, which, in turn, downregulates mTOR and initiates autophagy. Here we show that ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. ARHImediated downregulation of PI3K/AKT and Ras/ERK signaling also decreases phosphorylation of FOXo3a, which sequesters this transcription factor in the nucleus. Nuclear retention of FOXo3a induces ATG4 and MAP-LC3-I, required for maturation of autophagosomes, and also increases the expression of Rab7, required for fusion of autophagosomes with lysosomes. Following the knockdown of FOXo3a or Rab7, autophagolysosome formation was observed but was markedly inhibited, resulting in numerous enlarged autophagosomes. ARHI expression correlates with LC3 expression and FOXo3a nuclear localization in surgical specimens of ovarian cancer. Thus, ARHI contributes to the induction of autophagy through multiple mechanisms in ovarian cancer cells. Autophagy is a dynamic intracellular process that degrades organelles and long-lived cytosolic proteins by sequestration within double-membrane enclosed vesicles termed autophagosomes. Lysosomes fuse with autophagosomes to produce autolysosome. Within acidified autolysosome, hydrolases cleave proteins and lipids, releasing amino acids and fatty acids that can provide energy for cells in a nutrient-poor environment.1,2 While many of the steps involved in autophagy have been well described at a molecular level, regulation of these events in malignant mammalian cells is less well understood.Our group has identified a maternally imprinted tumor suppressor gene, DIRAS3, which regulates several steps in autophagy including induction and membrane elongation. Aplasia Ras homolog member I (ARHI) is an imprinted gene that is expressed from a single paternal allele in most normal tissues and that is downregulated in a fraction of carcinomas of the ovary, breast, lung, prostate, thyroid and pancreas. ARHI's downregulation in 460% of ovarian cancers is associated with decreased progression-free survival.3 Downregulation is achieved through multiple mechanisms, including loss of heterozygosity, DNA methylation, transcriptional regulation and shortened RNA half-life.4-14 ARHI encodes a 26 kDa GTPase with 50-60% homology to Ras and...

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MicroRNAs 221/222 and Genistein-Mediated Regulation of ARHI Tumor Suppressor Gene in Prostate Cancer

Cited by 140 publications

References 23 publications

miR-222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma

miR-222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma

Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion

ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7

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