RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells

Lin, Xiaojuan; Shen, Jianfeng; Peng, Dan; He, Xinhong; Xu, Congjian; Chen, Xiaojun; Tanyi, János L.; Montone, Kathleen T.; Fan, Yi; Huang, Qihong; Zhang, Lin; Zhong, Xiaorong

doi:10.1038/s41392-018-0026-5

Cited by 58 publications

(56 citation statements)

References 50 publications

(71 reference statements)

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“…In fact, in response to mitochondrial damage, the cell recruited the lysosome to degrade the damaged mitochondria. However, this protective mitophagy was significantly inhibited by ox‐LDL (Dasa et al, ; Lin et al, ). Therefore, our findings provide further insight into the mechanism of mitochondrial injury induced by the inflammatory response (Cui et al, ; Goiran et al, ), which also provide a potential target to increase mitochondrial resistance against inflammatory damage.…”

Section: Discussionmentioning

confidence: 99%

PTEN inhibition attenuates endothelial cell apoptosis in coronary heart disease via modulating the AMPK–CREB–Mfn2‐mitophagy signaling pathway

Wang

Zhao

et al. 2019

Journal Cellular Physiology

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Atherosclerosis (AS) is a major pathogenic factor in patients with cardiovascular diseases, and endothelial dysfunction (ED) plays a primary role in the occurrence and development of AS. In our study, we attempted to evaluate the role of phosphatase and tensin homolog (PTEN) in endothelial cell apoptosis under oxidized low-density lipoprotein (ox-LDL) stimulation and identify the associated mechanisms. The results of our study demonstrated that ox-LDL induced human umbilical vein endothelial cell (HUVEC) death via mitochondrial apoptosis, as evidenced by reduced mitochondrial potential, increased mitochondria permeability transition pore opening, cellular calcium overload, and caspase-9/-3 activation. In addition, ox-LDL also suppressed cellular energy production via downregulating the mitochondrial respiratory complex. Moreover, ox-LDL impaired HUVECs migration. Western blot analysis showed that PTEN expression was upregulated after exposure to ox-LDL and knockdown of PTEN could attenuate ox-LDL-mediated endothelial cell damage. Furthermore, we found that ox-LDL impaired mitophagy activity, whereas PTEN deletion could improve mitophagic flux and this effect relied on the activity of the AMPactivated protein kinase (AMPK)-cAMP-response element-binding protein (CREB)-Mitofusin-2 (Mfn2) axis. When the AMPK-CREB-Mfn2 pathway was inhibited, PTEN deletion-associated HUVECs protection was significantly reduced, suggesting that the AMPK-CREB-Mfn2-mitophagy axis is required for PTEN deletion-mediated endothelial cell survival under ox-LDL. Taken together, our results indicate that ox-LDL-induced endothelial cell damage is associated with PTEN overexpression, and inhibition of PTEN could promote endothelial survival via activating the AMPK-CREB-Mfn2-mitophagy signaling pathway. K E Y W O R D S AMPK-CREB-Mfn2 signaling pathway, endothelial cell dysfunction, Mfn2, mitophagy, ox-LDL, PTEN

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Section: Discussionmentioning

confidence: 99%

PTEN inhibition attenuates endothelial cell apoptosis in coronary heart disease via modulating the AMPK–CREB–Mfn2‐mitophagy signaling pathway

Wang

Zhao

et al. 2019

Journal Cellular Physiology

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“…Rs2153127, as one of instrumental variables of AAM in our MR study, is indicated to be associated with the expression of LIN28B in pituitary (https://www.gtexportal.org/home/snp/rs2153127). LIN28B was reported to be related to the proliferation, migration, and apoptosis of ovarian cancer . Further studies on variants associated with AAM or in the HPG axis may be beneficial to identify additional genetic variants for ovarian cancer risk.…”

Section: Discussionmentioning

confidence: 99%

“…LIN28B was reported to be related to the proliferation, migration, and apoptosis of ovarian cancer. 74,75 Further studies on variants associated with AAM or in the HPG axis may be beneficial to identify additional genetic variants for ovarian cancer risk. Additionally, the negative association between AAM and EOC risk could be explained by hormone-related "incessant ovulation" hypothesis, which supported increasing numbers of lifetime ovulations with higher risk of ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Age at menarche and epithelial ovarian cancer risk: A meta‐analysis and Mendelian randomization study

et al. 2019

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Age at menarche (AAM) was found to be associated with ovarian cancer risk in previous observational studies. However, the causality of this association remains unclear. Here, after systematic meta‐analyses, we performed two‐sample Mendelian randomization (MR) analyses to evaluate the causal effect of AAM in epithelial ovarian cancer (EOC) etiology. We performed meta‐analyses including 11 410 cases and 1 163 117 noncases to quantitatively evaluate the association between AAM and ovarian cancer risk. In MR analyses, we used 25 single nucleotide polymorphisms (SNPs) associated with AAM for Chinese and 390 SNPs for Europeans as instrumental variables. MR estimates were calculated using inverse‐variance weighted methods from 1044 cases and 1172 controls in a Chinese genome‐wide association study and validated by the Ovarian Cancer Association Consortium and Consortium of Investigators of Modifiers of BRCA1/2 studies with 29 396 cases and 68 502 controls of European ancestry. In meta‐analyses, we observed an inverse association (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93 to 1.00, P = 0.036) between per year older AAM and ovarian cancer risk in case–control studies, but no association was observed in cohort studies. In MR analyses, the OR of EOC risk per year increase in AAM was 0.81 (95% CI = 0.67 to 0.97, P = 0.026) in Chinese and 0.94 (95% CI = 0.90 to 0.98, P = 0.003) in Europeans, respectively. Our study supports a causal association between AAM and EOC risk.

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“…LIN28B, with its paralog LIN28A, plays pivotal roles in regulating multiple processes that shape normal development, including the cell cycle and apoptosis, self-renewal, glycolysis, and oxidative phosphorylation, among others. (5) (6) These same processes are often subverted in a variety of tumors; accordingly, LIN28B is deregulated in multiple tumor histotypes, including cancers of the colon (7) and ovary (8), Wilms tumor (9), germ cell tumors (10), and hepatocellular carcinomas. (11) Targeted LIN28B overexpression in respective murine tissues leads to the development of neuroblastoma (3), colon cancer (11) (12), and liver cancer (11), credentialing LIN28B as a bona fide oncogene.…”

Section: Introductionmentioning

confidence: 99%

LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

Chen

Cox

Annam

et al. 2019

Preprint

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Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, opposes the effects of LIN28B. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and selfrenewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7 and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B.Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.3

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RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells

Cited by 58 publications

References 50 publications

PTEN inhibition attenuates endothelial cell apoptosis in coronary heart disease via modulating the AMPK–CREB–Mfn2‐mitophagy signaling pathway

PTEN inhibition attenuates endothelial cell apoptosis in coronary heart disease via modulating the AMPK–CREB–Mfn2‐mitophagy signaling pathway

Age at menarche and epithelial ovarian cancer risk: A meta‐analysis and Mendelian randomization study

LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

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