Association of HOTAIR expression with PI3K/Akt pathway activation in adenocarcinoma of esophagogastric junction

Zhang, Hui; Meng, Xiangjiao

doi:10.1515/med-2016-0008

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…PI3K and mTOR signalling pathways control proliferation, differentiation, and survival of hematopoietic cells(59). Consistent with our studies, other studies indicated the potency of lncRNAs facilitating the cancer cell growth through mTOR and PI3K signalling pathways(36,47,60) yet reports on BCPALL subtypes are lacking. Considering the functional nexus between Phlike specific lncRNAs and the activation of pathways such as mTOR and PI3K signalling pathways, targeting those lncRNAs may be a promising novel therapeutic target for BCPALL subtypes.Our work additionally underscores the importance of epigenetic alterations in modulating lncRNAs transcriptional activities.…”

supporting

confidence: 90%

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

James

Schroêder

Neumann

et al. 2018

Preprint

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Recent studies implicated that long noncoding RNAs (lncRNAs) may play a role in the progression and development of acute lymphoblastic leukemia, however, this role is not yet clear. In order to unravel the role of lncRNAs associated with Bcell precursor Acute Lymphoblastic Leukemia (BCPALL) subtypes, we performed transcriptome sequencing and DNA methylation array across 82 BCPALL samples from three molecular subtypes (DUX4, Phlike, and Near Haploid or High Hyperdiploidy). Unsupervised clustering of BCPALL samples on the basis of their lncRNAs on transcriptome and DNA methylation profiles revealed robust clusters separating three molecular subtypes. Using extensive computational analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCPALL subtypespecific lncRNAs with altered expression and methylation patterns from three subtypes of BCPALL. By analyzing the coexpression of subtypespecific lncRNAs and proteincoding genes, we inferred key molecular processes in BCPALL subtypes. A strong correlation was identified between the DUX4 specific lncRNAs and activation of TGF and Hippo signaling pathways. Similarly, Phlike specific lncRNAs were β correlated with genes involved in activation of PI3KAKT, mTOR, and JAKSTAT signaling pathways. Interestingly, the relapsespecific differentially expressed lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we showed a set of epigenetically altered lncRNAs facilitating the expression of tumor genes located at their cis location. Overall, our study provides a comprehensive set of novel subtype and relapse specific lncRNAs in BCPALL. Our findings suggest a wide range of molecular pathways are associated with lncRNAs in BCPALL subtypes and provide a foundation for functional investigations that could lead to new therapeutic approaches. The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/365429 doi: bioRxiv preprint first posted online Jul. 9, 2018; Author SummaryAcute lymphoblastic leukemia is a heterogeneous blood cancer, with multiple molecular subtypes, and with high relapse rate. We are far from the complete understanding of the rationale behind these subtypes and high relapse rate. Long noncoding (lncRNAs) has emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. LncRNAs does not code for proteins and represent around 70% of human transcripts. Recently, there are a number of studies used lncRNAs expression profile in the classification of various cancers subtypes and displayed their correlation with genomic, epigenetic, pathological and clinical features in diverse cancers. Therefore, lncRNAs can account for heterogeneity and has independent prognostic value in various cancer subtypes.However, lncRNAs defining the molecular subtypes of BCPALL are not portrayed yet. Here, we describe a set of relapse and subtypespecific lncRNAs from three major BCPALL subtypes and define their potential functions and epigenetic regulation. Our data uncover ...

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supporting

confidence: 90%

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

James

Schroêder

Neumann

et al. 2018

Preprint

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“…Noncoding RNAs have received growing attention in recent years as regulators of oncogenic signalling pathways in oral cancer . The lncRNA HOTAIR and miR‐21 are reported to activate PI3K/Akt signalling by targeting PTEN, a tumour suppressor that inhibits PI3K . In this study, AXT downregulated both HOTAIR and miR‐21, underscoring its modulatory effects on the epigenome.…”

Section: Discussionmentioning

confidence: 62%

Astaxanthin inhibits hallmarks of cancer by targeting the PI3K/NF‐κΒ/STAT3 signalling axis in oral squamous cell carcinoma models

et al. 2019

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Aberrant activation of the PI3K/Akt signalling pathway, a major driving force of diverse cellular processes has been implicated in tumour development and progression. Here, we report that astaxanthin (AXT), a potent antioxidant ketocarotenoid prevents cancer hallmarks by inhibiting PI3K/Akt and the associated downstream NF‐κB and STAT‐3 signalling pathways in SCC131 and SCC4 oral cancer cells as well as in the hamster buccal pouch carcinogenesis model. Using small molecule inhibitors of NF‐κB, STAT‐3 and PI3K and by overexpression of PI3K, we provide evidence to show that AXT inhibits NF‐κB and STAT‐3 signalling and cancer hallmarks by restraining the kinase activity of PI3K/Akt. Additionally, AXT downregulated the noncoding RNAs (ncRNAs), miR‐21 and HOTAIR that influence PI3K/Akt signalling emphasising its modulatory effects on epigenetic regulation. Ethyl cellulose‐based AXT nanoparticles showed greater chemotherapeutic efficacy in the hamster oral carcinogenesis model compared to native AXT. We suggest that AXT prevents cell proliferation, apoptosis evasion, invasion and angiogenesis by intercepting the crosstalk between the PI3K/Akt, NF‐κB and STAT‐3 signalling circuits both in vitro and in vivo. Astaxanthin that abrogates the PI3K/Akt signalling axis, a central hub that orchestrates acquisition of cancer hallmarks is a promising candidate for anticancer drug development.

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“…Of late, ncRNAs have gained increasing attention as novel players that modulate oncogenic signalling pathways in oral cancer 55 . HOTAIR, a long non-coding RNA overexpressed in most human cancers including OSCCs activates PI3K/Akt signalling by inactivating the tumor suppressor PTEN, an inhibitor of PI3K 56 . On the other, miR-126 that negatively regulates the PI3K/Akt pathway by activating GSK3β is downregulated in OSCC cell lines and tissues 15 .…”

Section: Discussionmentioning

confidence: 99%

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

et al. 2018

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Of late, nimbolide, a limonoid from the neem tree (Azadirachta indica) has gained increasing research attention owing to its potent antiproliferative and apoptosis-inducing effects. The present study was designed to investigate the effect of nimbolide on autophagy and the time point at which the phosphorylation status of GSK-3β and PI3K dictate the choice between autophagy and apoptosis in SCC131 and SCC4 oral cancer cells. Additionally, we analysed changes in the expression of proteins involved in autophagy and apoptosis after therapeutic intervention with nimbolide in a hamster model of oral oncogenesis. Furthermore, we also demonstrate changes in the expression of key genes involved in apoptosis and autophagy during the stepwise evolution of hamster and human OSCCs. Nimbolide-induced stereotypical changes in oral cancer cells characteristic of both apoptosis and autophagy. Time-course experiments revealed that nimbolide induces autophagy as an early event and then switches over to apoptosis. Nimbolide negatively regulates PI3K/Akt signalling with consequent increase in p-GSK-3βTyr216, the active form of GSK-3β that inhibits autophagy. Downregulation of HOTAIR, a competing endogenous RNA that sponges miR-126 may be a major contributor to the inactivation of PI3K/Akt/GSK3 signalling by nimbolide. Analysis of key markers of apoptosis and autophagy as well as p-AktSer473 during sequential progression of hamster and human OSCC revealed a gradual evolution to a pro-autophagic and antiapoptotic phenotype that could confer a survival advantage to tumors. In summary, the results of the present study provide insights into the molecular mechanisms by which nimbolide augments apoptosis by overcoming the shielding effects of cytoprotective autophagy through modulation of the phosphorylation status of Akt and GSK-3β as well as the ncRNAs miR-126 and HOTAIR. Development of phytochemicals such as nimbolide that target the complex interaction between proteins and ncRNAs that regulate the autophagy/apoptosis flux is of paramount importance in cancer prevention and therapeutics.

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Association of HOTAIR expression with PI3K/Akt pathway activation in adenocarcinoma of esophagogastric junction

Cited by 15 publications

References 20 publications

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

Astaxanthin inhibits hallmarks of cancer by targeting the PI3K/NF‐κΒ/STAT3 signalling axis in oral squamous cell carcinoma models

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3β signalling pathway in oral cancer

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