Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma

Ky, Lin; H, Ye; Bw, Han; Wang, Wen-Tao; Pp, Wei; He, Bin; Xj, Li; Yq, Chen

doi:10.1038/onc.2015.396

Cited by 62 publications

(59 citation statements)

References 54 publications

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“…Generally, IL-6 was secreted by noncancer stem cells in low-attachment culture conditions and enriched Oct4 gene expression by activating the IL-6R/JAK/STAT3 signaling pathway in chronic inflammatory disease, such as cholangiocarcinoma [47, 48]. Our previously study also found treatment of CAA cells with IL-6 can active paracrine IL-6/STAT3 pathway in inflammation and CCA initiation [49]. IL-6 is a multifunctional inflammatory cytokine that plays a major role in the response of cholangiocytes to inflammation [40, 50]; and increased concentrations of IL-6 during inflammation in the biliary tract stimulates several pathways, including the JAK-STAT pathway, the p38 MAPK pathway, the ERK pathway, and the PI3-kinase pathway, and is involved in survival and growth of malignant cholangiocytes [40, 51].…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of studies have realized that inflammation is one of important responses to the oxidative stress in many diseases, such as the gut [64], lung [65], pancreatitis [66], colorectal cancer [49], and cholangiocarcinoma [67]. Fernanda et al also reviewed a total of 1332 studies initially identified that TNF-a, IL-8, IL-6, IL-1b, and NF-κB were the main inflammatory mediators and oxidative stress markers [65], suggesting that the oxidative stress made a great contribution in inflammatory in the initiation or progression of disease.…”

Section: Discussionmentioning

confidence: 99%

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LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

et al. 2016

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BackgroundLong non-coding RNAs (lncRNAs) are known to play important roles in different cell contexts, including cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis, associated with chronic inflammation and damage to the biliary epithelium. The aim of the study is to identify if any lncRNA might associate with inflammation or oxidative stress in CCA and regulate the disease progression.MethodsIn this study, RNA-seqs datasets were used to identify aberrantly expressed lncRNAs. Small interfering RNA and overexpressed plasmids were used to modulate the expression of lncRNAs, and luciferase target assay RNA immunoprecipitation (RIP) was performed to explore the mechanism of miRNA-lncRNA sponging.ResultsWe firstly analyzed five available RNA-seqs datasets to investigate aberrantly expressed lncRNAs which might associate with inflammation or oxidative stress. We identified that two lncRNAs, H19 and HULC, were differentially expressed among all the samples under the treatment of hypoxic or inflammatory factors, and they were shown to be stimulated by short-term oxidative stress responses to H2O2 and glucose oxidase in CCA cell lines. Further studies revealed that these two lncRNAs promoted cholangiocyte migration and invasion via the inflammation pathway. H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.ConclusionsOur study revealed that H19 and HULC, up-regulated by oxidative stress, regulate CCA cell migration and invasion by targeting IL-6 and CXCR4 via ceRNA patterns of sponging let-7a/let-7b and miR-372/miR-373, respectively. The results suggest that these lncRNAs might be the chief culprits of CCA pathogenesis and progression. The study provides new insight into the mechanism linking lncRNA function with CCA and may serve as novel targets for the development of new countermeasures of CCA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0348-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

et al. 2016

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“…Both miR-99a and miR-491 may play different roles in various cancers as they regulated different target genes. The miR-99a has been reported to regulate resistance in breast cancer 18, leukemia 19, neck squamous cell carcinoma 20, germ cell tumor 21, pancreatic ductal adenocarcinoma 22, cholangiocarcinoma23, etc. The relation between miR-491 and liver cancer 24, colorectal cancer 25, ovarian carcinoma 26, pancreatic cancer 27, oral squamous cell carcinoma 28, non-small cell lung cancer 29, etc has also been verified.…”

Section: Discussionmentioning

confidence: 99%

MiR-99a and MiR-491 Regulate Cisplatin Resistance in Human Gastric Cancer Cells by Targeting CAPNS1

Zhang¹,

Xu²,

Ni³

et al. 2016

Int. J. Biol. Sci.

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Cisplatin is the first-line agent utilized for the clinical treatment of a wide variety of solid tumors including gastric cancer. However, the intrinsic or acquired cisplatin resistance is often occurred in patients with gastric cancer and resulted in failure of cisplatin therapy. In order to investigate if miRNA involves in cisplatin resistance of human gastric cancer, we first screened and compared the expression of miRNAs between cisplatin resistant gastric cancer cell lines SGC-7901/DDP and BGC-823/DDP and their sensitive parental cells by miRNAs microarray and followed by analysis of 2D-GE/MS to identify their target proteins. We found both miR-99a and miR-491 were upregulated while their target gene calpain small subunit 1 (CAPNS1) was downregulated in resistant gastric cancer cells. Dual-luciferase- reporter assays with wild-type and mutated CAPNS1 3'-UTR confirmed their specificity of targeting. Inhibition of miR-99a and miR-491, or overexpress CAPNS1 can enhance cisplatin sensitivity of the resistant cells while transfection of two miRNAs' mimics or si-CAPNS1 in the sensitive cells can induce their resistance. Moreover, our results demonstrated CAPNS1 positively regulated calpain1 and calpain2, the catalytic subunits of CAPNS1, and cleaved caspase3 which further cleaved PARP1 and directly induced apoptosis. Therefore, miR-99a and miR-491 might be work as novel molecules regulate cisplatin resistance by directly targeting CAPNS1 associated pathway in human gastric cancer cells.

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“…miR-125b has also been shown to promote stem cell-like properties in cholangiocarcinoma 62 and expand progenitor cell populations in acute megakaryoblastic leukemia 63 . Furthermore, miR-125b is significantly enriched in hair follicle stem cells and promotes initiation and malignant progression of skin tumors 45,64 .…”

Section: Discussionmentioning

confidence: 99%

cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation

et al. 2016

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Elucidating the mechanisms involved in sensitizing radioresistant tumors to ionizing radiation (IR) treatments while minimizing injury to surrounding normal tissue is an important clinical goal. Due to their sequence-derived specificity and properties as gene regulators in IR-affected pathways, microRNAs (miRNAs) could serve as adjuvant therapeutic agents that alter cellular sensitivity to radiation treatment. To identify radiosensitizing miRNAs, we initially utilized the C. elegans vulval cell model, an in vivo system developed to study IR-dependent radiosensitivity as a measure of clonogenic cell death. We tested several candidate miRNA deletion mutants post γ-irradiation and identified cel-mir-237 as a miRNA which when deleted caused animals to be more resistant to IR, while cel-mir-237 overexpressing strains were IR-sensitive. Additionally, wild-type animals downregulated cel-mir-237 levels post IR in a time-dependent manner. We identified jun-1 (JUN transcription factor homolog) as a novel target of cel-mir-237. Specifically, jun-1 transcript levels increased in wild-type animals post-γ-irradiation, and loss of cel-mir-237 also resulted in higher jun-1 expression. As expected, loss of jun-1 resulted in IR sensitivity, similar to the phenotype of cel-mir-237 overexpressors. Since miR-237 is the homologue of human miR-125, we validated our findings in MCF-7 and MDA-MB-231 breast cancer cell lines, which harbor lower hsa-miR-125b levels than normal HMECs. Forced expression of hsa-miR-125b in these cells resulted in radiosensitivity, as seen by reduced clonogenic survival, enhanced apoptotic activity, and enhanced senescence post IR. Finally, re-expression of c-JUN in MDA-MB-231 cells promoted radio-resistance and abrogated miR-125-mediated radio-sensitization. Our findings suggest that overexpression of cel-mir-237 and its homologue, hsa-miR-125b, functions as sensitizers to γ-irradiation in both a nematode in vivo model and breast cancer cells, and could potentially be utilized as an adjuvant therapeutic to enhance radiation sensitivity.

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Genome-wide screen identified let-7c/miR-99a/miR-125b regulating tumor progression and stem-like properties in cholangiocarcinoma

Cited by 62 publications

References 54 publications

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

MiR-99a and MiR-491 Regulate Cisplatin Resistance in Human Gastric Cancer Cells by Targeting CAPNS1

cel-mir-237 and its homologue, hsa-miR-125b, modulate the cellular response to ionizing radiation

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