Copy Number Gain of hsa-miR-569 at 3q26.2 Leads to Loss of TP53INP1 and Aggressiveness of Epithelial Cancers

Chaluvally‐Raghavan, Pradeep; Zhang, Fan; Pradeep, Sunila; Hamilton, Mark; Zhao, Xi; Rupaimoole, Rajesha; Moss, Tyler J.; Lu, Yiling; Yu, Shuangxing; Pecot, Chad V.; Aure, Miriam Ragle; Peuget, Sylvain; Rodríguez-Aguayo, Cristian; Han, Hee Dong; Zhang, Dong; Venkatanarayan, Avinashnarayan; Krohn, Marit; Kristensen, Vessela N.; Gagea, Mihai; Ram, Prahlad T.; Liu, Wenbin; López-Berestein, Gabriel; Lorenzi, Philip L.; Børresen-Dale, Anne Lise; Chin, Koei; Gray, Joe W.; Dusetti, Nelson; McGuire, Sean E.; Flores, Elsa R.; Sood, Anil K.; Mills, Gordon B.

doi:10.1016/j.ccell.2014.10.010

Cited by 44 publications

(45 citation statements)

References 43 publications

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“…Indeed, miR551b-3p leads to recruitment of RNA Polymerase II (RNA-Pol-II or RPOL2) and the Twist1 transcription factor to the STAT3 promoter and increases STAT3 mRNA levels. Consistent with a key role of miR551b-3p and STAT3 in ovarian cancer pathophysiology, anti-miR551b incorporated into neutral nano-liposomes (Chaluvally-Raghavan et al, 2014; Landen et al, 2005) markedly decreased ovarian cancer growth in vivo .…”

Section: Introductionsupporting

confidence: 56%

“…To determine whether miR551b-3p altered tumor growth in vivo , nude mice bearing IGROV1 tumors were treated with intraperitoneal injection of miR551b-3p incorporated in neutral 1,2-dioleoyl- sn -glycero-3-phosphotidylcholine (DOPC) nano-liposomes (Chaluvally-Raghavan et al, 2014; Landen et al, 2005). Intraperitoneal injection of miR551b-3p into nude mice markedly increased the number of tumor nodules and tumor weight (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3q26 amplification is a frequent event in High Grade Serous Epithelial Ovarian Cancer (HGSEOC) (Bell et al, 2011; Chaluvally-Raghavan et al, 2014; Shayesteh et al, 1999), which is the most common and aggressive form of ovarian cancer. We have demonstrated that the 3q26 CNA is complex, resulting in amplification and aberrant function of several oncogenes including PIK3CA (Shayesteh et al, 1999), PKCι (Eder et al, 2005), Mecom (EVI1 and MDS1/EVI1) (Nanjundan et al, 2007) and a non-coding RNA, miR-569 (Chaluvally-Raghavan et al, 2014). While the coding genes in the 3q26.2 amplicon are well-studied, the potential roles of microRNAs (miRNA or miR) located at the 3q26 locus remain poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

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Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer

Chaluvally‐Raghavan¹,

Jeong²,

Pradeep³

et al. 2016

Cell Reports

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SUMMARY 3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro and in vivo. miR551b-3p up-regulates STAT3 protein levels with STAT3 being required for the effects of miR551b-3p on cell proliferation. Rather than decreasing levels of target mRNA as expected, we demonstrate that miR551b-3p binds a complementary sequence on the STAT3 promoter recruiting RNA Polymerase II and the TWIST1 transcription factor to activate STAT3 transcription and thus directly upregulates STAT3 expression. Furthermore, anti-miR551b reduced STAT3 expression in ovarian cancer cells in vitro and in vivo and reduced ovarian cancer growth in vivo. Together our data demonstrates a role for miR551b-3p in transcriptional activation. Thus miR551b-3p represents a promising candidate biomarker and therapeutic target in ovarian cancer.

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Section: Introductionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer

Chaluvally‐Raghavan¹,

Jeong²,

Pradeep³

et al. 2016

Cell Reports

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“…Short hairpin-mediated lincRNA-3q depletion was associated with differential expression of 371 (174 up; 197 down) and 904 genes (428 up; 476 down) in CAL-1 and U937 cells, respectively, thus suggestive of a cell context-dependent role for lincRNA-3q in both gene activation and repression. Among the lincRNA-3q regulated genes in BPDCN CAL-1 cells were TCL1B, 47 HOXB4, 48 and TP53INP1, a tumor suppressor gene 49 ( Figure 4D). Similarly, E2F family members (E2F7 and E2F8) known to negatively regulate E2F transcriptional activity were modulated by lincRNA-3q knockdown in U937 cells 50 (supplemental Figure 4E).…”

Section: Gcr-fp(-) Gcr-fp(+)mentioning

confidence: 99%

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Emadali

Hoghoughi

Duley

et al. 2016

Blood

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Key Points• NR3C1 haploinsufficiency is found in patients with a plasmacytoid dendritic cell neoplasm characterized by very poor clinical outcome.• Overexpression of lincRNA3q is a consistent feature of malignant cells in these patients and can be abrogated by BET protein inhibition.Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P 5 .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN. (Blood. 2016;127(24):3040-3053)

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“…Further studies have shown that altered ncRNA functions initiated by genetic or regulatory changes play an important role in tumorigenesis [22][23][24][25][26][27].…”

mentioning

confidence: 99%

Mining the coding and non-coding genome for cancer drivers

Drubay

Michiels

et al. 2015

Cancer Letters

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Copy Number Gain of hsa-miR-569 at 3q26.2 Leads to Loss of TP53INP1 and Aggressiveness of Epithelial Cancers

Cited by 44 publications

References 43 publications

Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer

Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Mining the coding and non-coding genome for cancer drivers

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