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Open accessJournal ArticleDOI: 10.1038/S41419-021-03523-Z

Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop in melanoma.

04 Mar 2021-Cell Death and Disease (Springer Science and Business Media LLC)-Vol. 12, Iss: 3, pp 245-245
Abstract: The long noncoding RNA, LINC00518, is highly expressed in various types of cancers and is involved in cancer progression. Although LINC00518 promotes the metastasis of cutaneous malignant melanoma (CMM), the mechanism underlaying its effects on CMM radiosensitivity remains unclear. In this study, LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which increased sensitivity to radiotherapy via inhibition of the hypoxia-inducible factor 1α (HIF-1α)/lactate dehydrogenase A glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase 2, which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signaling with initially activated glycolysis and radioresistance in CMM cells was impaired by Santacruzamate A, a histone deacetylase inhibitor, and 2-deoxy-D-glucose, a glycolytic inhibitor. Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumor model. In conclusion, LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our study, may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.

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Topics: Radioresistance (55%), Histone deacetylase 2 (54%), Histone deacetylase inhibitor (53%) ... show more

5 results found

Open accessJournal ArticleDOI: 10.3390/IJMS22147261
Seung Wan Son1, Ba Da Yun1, Mun Gyu Song1, Jin Kyeong Lee1  +3 moreInstitutions (2)
Abstract: Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer.

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Topics: Cancer (53%), Long non-coding RNA (53%), Metastasis (51%)

2 Citations

Open accessJournal ArticleDOI: 10.2147/CMAR.S314502
Peng Huang1, Shaomi Zhu1, Xin Liang1, Qinxiu Zhang1  +3 moreInstitutions (1)
Abstract: Cancer cells exhibit distinct metabolic characteristics that employ glycolysis to provide energy and intermediary metabolites. This aberrant metabolic phenotype favors cancer progression. LncRNAs are transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs contribute to cancer progression and therapeutic resistance and affect aerobic glycolysis via multiple mechanisms, including modulating glycolytic transporters and enzymes. Further, dysregulated signaling pathways are vital for glycolysis. In this review, we highlight regulatory mechanisms for lncRNAs in aerobic glycolysis that provide novel insights into cancer development. Moreover, a comprehensive understanding of the regulatory mechanisms of lncRNAs in aerobic glycolysis can provide new strategies for clinical cancer management.

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Topics: Anaerobic glycolysis (58%)

1 Citations

Book ChapterDOI: 10.1007/978-981-16-0364-8_13
01 Jan 2021-
Abstract: Skin carcinoma is categorized into melanoma and non-melanoma. Melanoma is among the highly aggressive and deadly forms of skin cancer. Melanoma is frequently associated with metastasis and therapeutic resistance. The combined immunotherapy and targeted therapies have emerged as attractive therapeutic options. However, the efficacy of these therapies is limited to advanced-stage melanoma and those who often acquire resistance. Over the years, the molecular bases of melanoma have been unraveled, which led to establishing specific and reliable biomarkers for the diagnosis, prognosis, and therapy. A good strategy in finding novel cancer targets could include shifting from the protein-translating regions to the genome’s non-coding regions. The non-coding regions constitute approximately 98% of the genome. The microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two major classes of non-coding RNAs. Apart from coding RNA’s, lncRNAs have also been attributed to exhibit proto-oncogenic and tumor suppressor roles in various cancers, including melanoma. This chapter summarizes the recent advancement of lncRNAs concerning diagnosis, prognosis, and therapy of melanoma.

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Topics: Skin cancer (57%), Cancer (54%), Melanoma (53%)

Open accessJournal ArticleDOI: 10.3390/CANCERS13194848
Michal Wozniak1, Malgorzata Czyz1Institutions (1)
28 Sep 2021-Cancers
Abstract: Melanoma is the most lethal skin cancer, with increasing incidence worldwide. The molecular events that drive melanoma development and progression have been extensively studied, resulting in significant improvements in diagnostics and therapeutic approaches. However, a high drug resistance to targeted therapies and adverse effects of immunotherapies are still a major challenge in melanoma treatment. Therefore, the elucidation of molecular mechanisms of melanomagenesis and cancer response to treatment is of great importance. Recently, many studies have revealed the close association of long noncoding RNAs (lncRNAs) with the development of many cancers, including melanoma. These RNA molecules are able to regulate a plethora of crucial cellular processes including proliferation, differentiation, migration, invasion and apoptosis through diverse mechanisms, and even slight dysregulation of their expression may lead to tumorigenesis. lncRNAs are able to bind to protein complexes, DNA and RNAs, affecting their stability, activity, and localization. They can also regulate gene expression in the nucleus. Several functions of lncRNAs are context-dependent. This review summarizes current knowledge regarding the involvement of lncRNAs in melanoma. Their possible role as prognostic markers of melanoma response to treatment and in resistance to therapy is also discussed.

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Topics: Targeted therapy (53%)

Open accessJournal ArticleDOI: 10.1016/J.BIOPHA.2021.111873
Abstract: Adaptation to the loss of O2 is regulated via the activity of hypoxia-inducible factors such as Hypoxia-Inducible Factor-1 (HIF-1). HIF-1 acts as a main transcriptional mediator in the tissue hypoxia response that regulates over 1000 genes related to low oxygen tension. The role of HIF-1α in oncogenic processes includes angiogenesis, tumor metabolism, cell proliferation, and metastasis, which has been examined in various malignancies, such as melanoma. Melanoma is accompanied by a high death rate and a cancer type whose incidence has risen over the last decades. The linkage between O2 loss and melanogenesis had extensively studied over decades. Recent studies revealed that HIF-1α contributes to melanoma progression via different signaling pathways such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/β-catenin, Notch, and NF-κB. Also, various microRNAs (miRs) are known to mediate the HIF-1α role in melanoma. Therefore, HIF-1α offers a diagnostic/prognostic biomarker and a candidate for targeted therapy in melanoma.

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Topics: PI3K/AKT/mTOR pathway (56%), Wnt signaling pathway (54%), MAPK/ERK pathway (54%) ... show more

63 results found

Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.02.013
Douglas Hanahan1, Robert A. Weinberg2Institutions (2)
04 Mar 2011-Cell
Abstract: The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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42,275 Citations

Open accessJournal ArticleDOI: 10.1200/JCO.2009.23.4799
Abstract: Purpose To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. Methods The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Results Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm 2 ), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.

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Topics: Cutaneous melanoma (60%), Melanoma (51%), Stage (cooking) (50%)

4,049 Citations

Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.07.014
Leonardo Salmena1, Laura Poliseno1, Yvonne Tay1, Lev Kats1  +1 moreInstitutions (1)
05 Aug 2011-Cell
Abstract: Here, we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long noncoding RNAs "talk" to each other using microRNA response elements (MREs) as letters of a new language. We propose that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer.

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Topics: Competing endogenous RNA (57%), Non-coding RNA (55%), Pseudogene (51%) ... show more

3,999 Citations

Journal ArticleDOI: 10.1126/SCIENCE.1175371
14 Aug 2009-Science
Abstract: Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technological limitations have so far prevented a global analysis of lysine acetylation's cellular roles. We used high-resolution mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.

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Topics: Acetylation (61%), Acetyllysine (61%), Chromatin remodeling (57%) ... show more

3,449 Citations

Journal ArticleDOI: 10.1038/NPROT.2006.339
01 Jan 2006-Nature Protocols
Abstract: Clonogenic assay or colony formation assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony. The colony is defined to consist of at least 50 cells. The assay essentially tests every cell in the population for its ability to undergo "unlimited" division. Clonogenic assay is the method of choice to determine cell reproductive death after treatment with ionizing radiation, but can also be used to determine the effectiveness of other cytotoxic agents. Only a fraction of seeded cells retains the capacity to produce colonies. Before or after treatment, cells are seeded out in appropriate dilutions to form colonies in 1-3 weeks. Colonies are fixed with glutaraldehyde (6.0% v/v), stained with crystal violet (0.5% w/v) and counted using a stereomicroscope. A method for the analysis of radiation dose-survival curves is included.

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Topics: Clonogenic assay (64%), Population (52%)

2,700 Citations