A crucial requirement for Hedgehog signaling in small cell lung cancer

Park, Kwon Sik; Martelotto, Luciano G.; Peifer, Martin; Sos, Martin L.; Karnezis, Anthony N.; Mahjoub, Moe R.; Bernard, Katie; Conklin, Jamie F.; Szczepny, Anette; Yuan, Jing; Guo, Ribo; Ospina, Beatrice; Falzon, Jeanette; Bennett, Samara; Brown, Tracey; Marković, Ana; Devereux, Wendy L.; Ocasio, Cory A.; Chen, James; Stearns, Tim; Thomas, Roman K.; Dorsch, Marion; Buonamici, Silvia; Watkins, D. Neil; Peacock, Craig D.; Sage, Julien

doi:10.1038/nm.2473

Cited by 217 publications

(213 citation statements)

References 40 publications

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“…Molecular profiling of the most common small cell carcinoma, small cell lung cancer, suggests that there is a stem cell component to the disease. Small cell lung cancer exhibits SOX2 amplification in 34% of patients and activation of hedgehog signaling (62,63). Similarly, immunohistochemistry has identified SOX2 expression in a majority of patients with metastatic NEPC (50).…”

Section: Discussionmentioning

confidence: 99%

A basal stem cell signature identifies aggressive prostate cancer phenotypes

Smith

Sokolov

Uzunangelov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

177

172

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Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACSpurified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organconfined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.RNA-seq | prostate cancer | stem cell signature | basal cell | neuroendocrine prostate cancer

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Section: Discussionmentioning

confidence: 99%

A basal stem cell signature identifies aggressive prostate cancer phenotypes

Smith

Sokolov

Uzunangelov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

177

172

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“…Moreover, JU may act on more than 10 pathways, which may contribute to the pure synergistic mechanism (Supplement Table 2). Some of these new pathways were involved in inflammatory immunity (IL-18 Signaling, Actin Cytoskeleton Signaling, Glucocorticoid Receptor Signaling, Lymphotoxin B Receptor Signaling, and IL-15 Signaling [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] [69][70][71][72][73][74][75][76][77] . Therefore, we propose that the pure synergistic mechanism is focused on inflammation, immune responses, apoptosis, and nervous system development ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Wang

et al. 2015

Acta Pharmacol Sin

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Aim: Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds. Methods: Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis. Results: In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function. Conclusion: The pure synergism between UA and JA underlies 10 new core pathways and 3 new core functions, which are involved in inflammation, immune responses, apoptosis and nervous system development.

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“…To investigate a role for SHH in NR2F2 and CTNNB1 regulation, primary cultures of myometrial and fibroid SMC (nZ6) were grown to confluence, serum-starved (as described earlier) and treated with SHH conditioned media (CM) in DMEM/1% FCS for 24 h (Park et al 2011). SHH CM was prepared as described previously (Ingram et al 2002, Hochman et al 2006, Park et al 2011.…”

Section: Shh Studymentioning

confidence: 99%

“…SHH CM was prepared as described previously (Ingram et al 2002, Hochman et al 2006, Park et al 2011. Briefly, media were collected from SHHN-923 cells, which were transfected to secrete active SHH (N-terminal domain) in a pMT21 (pSHH-N-PMT21) plasmid.…”

Section: Shh Studymentioning

confidence: 99%

“…The HH pathway is important in many normal and abnormal cellular functions, including embryonic development, stem cell proliferation and cancer genesis (reviewed by Varjosalo & Taipale (2008), Choi et al (2011), Harris et al (2011) and Park et al (2011)). The HH pathway is also crucial to the development of reproductive tract (Franco & Yao 2012), uterine function (Takamoto et al 2005, Lee et al 2006a) and uterine malignancies (Feng et al 2007, Kim et al 2009).…”

Section: Nr2f2 and Ctnnb1 In Uterine Fibroidsmentioning

confidence: 99%

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Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

Zaitseva¹,

Holdsworth-Carson²,

Waldrip³

et al. 2013

Reproduction

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Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures.In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.

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A crucial requirement for Hedgehog signaling in small cell lung cancer

Cited by 217 publications

References 40 publications

A basal stem cell signature identifies aggressive prostate cancer phenotypes

A basal stem cell signature identifies aggressive prostate cancer phenotypes

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

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