Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis

Chang, Renxu; Song, Lele; Xu, Yi; Wu, Yanjun; Dai, Cheng; Wang, Xinyu; Sun, Xia; Hou, Yayi; Li, Wei; Zhan, Xi; Zhan, Lixing

doi:10.1038/s41467-018-05852-8

Cited by 94 publications

(95 citation statements)

References 64 publications

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“…The P65 pathway has been found to mediate the process of ischemic brain injury, hence a promising therapeutic target for ischemic stroke, and ikB as the master inhibitor of the P65 pathway, to have a degrading function during pathway activation (Hayden et al, 2008;Tu et al, 2014;Wang et al, 2017). A recent study has shown that linagliptin could suppress the expression of phosphorylated J A K 2 , p h o s p h o r y l a t e d S T A T 3 a n d P 6 5 t o c o n f e r neuroprotection (Marotta et al, 2011;Chang et al, 2018;Elbaz Eman et al, 2018). These results are similar to those which were found in the current study, which suggests the effects of inflammation reduction and neuroprotection.…”

Section: Discussionsupporting

confidence: 91%

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Sun

Qiu

et al. 2020

Front. Pharmacol.

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Stachydrine, a constituent of Leonurus japonicus Houtt which also called Japanese motherwort has been shown to improve vascular microcirculation and ameliorate endothelial dysfunction. This study investigated the neuroprotective effect of stachydrine. Male Sprague-Dawley (SD) rats were randomly divided into sham, control, and stachydrine groups. The neurological deficit score was evaluated and the infarct size of the brain was measured using 2,3,5-triphenyltetra-zolium (TTC) chloride staining assay, and the pathological changes in the brain tissues were examined by HE staining. Nissl and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining were performed to assess the numbers of Nissl bodies and the levels of apoptosis in the neurons. The activities of superoxide dismutase (SOD) and the levels of malondialdehyde (MDA) were also measured. The release of inflammatory factors IL-1b and TNF-a were detected by Enzyme-linked immunosorbent assay (ELISA). Compared with the control group, the stachydrine group showed a significant prevention of neurological deficit, as indicated by the reduced infarct volume in the brain. Moreover, the stachydrine treatment reduced the activities of SOD, the levels of MDA and decreased the amount of IL-1b, and TNF-a, indicating that it could function to decrease the level of inflammation, thus reducing brain damage. The ischemic stroke model of PC12 cells was prepared via oxygen-glucose deprivation (OGD) protocol for 6 h. The expression of P65 and JAK2/STAT3 signaling pathway related proteins was measured by western blot. The treatment group was found to have the survival rate of PC12 cells improved and the release of inflammatory factors reduced when compared with the OGD group. This study demonstrated that stachydrine could improve nerve function by inhibiting the phosphorylation of P65/JAK2 and STAT3. FIGURE 1 | The chemical structure of stachydrine. Stachydrine (purity> 97%) purchased from Dalian Meilun Biology Technology Co. (Dalian, China). Li et al. Stachydrine Protects Against Cerebral Ischemia-Reperfusion InjuryFrontiers in Pharmacology | www.frontiersin.org February 2020 | Volume 11 | Article 64 absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Section: Discussionsupporting

confidence: 91%

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Sun

Qiu

et al. 2020

Front. Pharmacol.

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“…Over the years it has been questioned whether CFS genes were or not genuine cancer gene targets or mere bystanders . Evidence from multiple studies has accumulated suggesting that indeed WWOX behaves as a low‐penetrance tumor suppressor with far more significant roles for affecting tumor progression rather than initiation in specific tumor types . Interestingly, loss of WWOX function has recently been associated with abnormalities in DNA damage repair (DDR), increased genomic instability, and resistance to chemoradiotherapy .…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] Evidence from multiple studies has accumulated suggesting that indeed WWOX behaves as a low-penetrance tumor suppressor with far more significant roles for affecting tumor progression rather than initiation in specific tumor types. [15][16][17][18][19] Interestingly, loss of WWOX function has recently been associated with abnormalities in DNA damage repair (DDR), increased genomic instability, and resistance to chemoradiotherapy. 20,21 In conjunction, the described observations place WWOX both as a target of and a contributor to genomic instability.…”

mentioning

confidence: 99%

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

Hussain

Liu

Shrock

et al. 2018

Genes Chromosomes & Cancer

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WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1‐q23.2 and containing FRA16D, the second most common chromosomal fragile site. FRA16D is a hot spot of genomic instability, prone to breakage and for causing germline and somatic copy number variations (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian, and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma. WWOX is also a common target for translocations in multiple myeloma. By mapping R‐loop (RNA:DNA hybrid) forming sequences (RFLS) we observe this to be a consistent feature aligning with germline and somatic CNV break points at the edges and core of FRA16D spanning from introns 5 to 8 of WWOX. Germline CNV polymorphisms affecting WWOX are extremely common in humans across different ethnic groups. Importantly, structural variants datasets allowed us to identify a specific hot spot for germline duplications and deletions within intron 5 of WWOX coinciding with the 5′ edge of the FRA16D core and various RFLS. Recently, multiple pathogenic CNVs spanning WWOX have been identified associated with neurological conditions such as autism spectrum disorder, infantile epileptic encephalopathies, and other developmental anomalies. Loss of WWOX function has recently been associated with DNA damage repair abnormalities, increased genomic instability, and resistance to chemoradiotherapy. The described observations place WWOX both as a target of and a contributor to genomic instability. Both of these aspects will be discussed in this review.

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“…Our data indicated that the CCD of STAT3 was essential for the interaction with ASRPS. Previous studies indicate that the CCD of STAT3 is essential for auto-phosphorylation (Ma et al, 2003; Zhang et al, 2000), and certain proteins could inhibit STAT3 activation by binding to STAT3 CCD domain (Chang et al, 2018; Mattagajasingh et al, 2012). Even K116, a STAT3 allosteric inhibitor, inhibited STAT3 phosphorylation at Tyr705 by binding to the CCD of STAT3 (Huang et al, 2018a).…”

Section: Discussionmentioning

confidence: 99%

“…TNBC is the most aggressive subtype of BC and is associated with worst prognosis and overall survival (OS; Son et al, 2019). It is characterized by high cell proliferation, poor cellular differentiation, and more frequent disease recurrence (Chang et al, 2018). Compared with non-TNBC, TNBC patients have poor prognosis, including higher nuclear grade, increased incidence of lung and brain metastases, and shorter recurrence-free interval.…”

Section: Introductionmentioning

confidence: 99%

LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis

Wang

Zhu

et al. 2019

Journal of Experimental Medicine

150

101

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Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60–aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.

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Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis

Cited by 94 publications

References 64 publications

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

Protective Effect of Stachydrine Against Cerebral Ischemia-Reperfusion Injury by Reducing Inflammation and Apoptosis Through P65 and JAK2/STAT3 Signaling Pathway

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis

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