bims-meluca 2019-11-24 papers

PET Clin. 2020 Jan;pii: S1556-8598(19)30079-3. [Epub ahead of print]15(1): 55-63

18F-Fluorodeoxyglucose PET in Locally Advanced Non-small Cell Lung Cancer: From Predicting Outcomes to Guiding Therapy.

N Patrik Brodin, Wolfgang A Tomé, Tony Abraham, Nitin Ohri.

PET using 18-fluorodeoxyglucose (FDG) has become an important part of the work-up for non-small cell lung cancer (NSCLC). This article summarizes advancements in using FDG-PET for patients with locally advanced NSCLC treated with definitive radiation therapy (RT). This article discusses prognostication of outcome based on pretreatment or midtreatment PET metrics, using textural image features to predict treatment outcomes, and using PET to define RT target volumes and inform RT dose modifications. The role of PET is evolving and is moving toward using quantitative image information, with the overarching goal of individualizing therapy to improve outcomes for patients with NSCLC.

Keywords: Non–small cell lung cancer; PET; Radiation therapy

DOI: https://doi.org/10.1016/j.cpet.2019.08.009

Cell Commun Signal. 2019 Nov 21. 17(1): 152

ΗΙF1α, EGR1 and SP1 co-regulate the erythropoietin receptor expression under hypoxia: an essential role in the growth of non-small cell lung cancer cells.

Tianhong Su, Pi Liu, Xinyu Ti, Shouzhen Wu, Xiaochang Xue, Zenglu Wang, Elhardji Dioum, Qiuyang Zhang.

BACKGROUND: Overexpression of erythropoietin (EPO) and EPO receptor (EPO-R) is associated with poor prognosis in non-small-cell lung carcinoma (NSCLC). Hypoxia, a potent EPO inducer, is a major stimulating factor in the growth of solid tumors. However, how EPO-R expression is regulated under hypoxia is largely unknown.
METHODS: The role of EPO-R in NSCLC cell proliferation was assessed by RNA interference in vitro. Luciferase reporter assays were performed to map the promoter elements involved in the EPO-R mRNA transcription. Nuclear co-immunoprecipitation and chromatin immunoprecipitation were performed to assess the interaction among transcription factors HIF1α, SP1, and EGR1 in the regulation of EPO-R under hypoxia. The expression of key EPO-R transcription factors in clinical specimens were determined by immunohistochemistry.
RESULTS: Hypoxia induced a dosage and time dependent EPO-R mRNA expression in NSCLC cells. Knockdown of EPO-R reduced NSCLC cell growth under hypoxia (P < 0.05). Mechanistically, a SP1-EGR1 overlapped DNA binding sequence was essential to the hypoxia induced EPO-R transcription. In the early phase of hypoxia, HIF1α interacted with EGR1 that negatively regulated EPO-R. With the exit of EGR1 in late phase, HIF1α positively regulated EPO-R expression through additive interaction with SP1. In clinical NSCLC specimen, SP1 was positively while EGR1 was negatively associated with active EPO-R expression (P < 0.05).
CONCLUSIONS: HIF1α, SP1 and EGR1 mediated EPO-R expression played an essential role in hypoxia-induced NSCLC cell proliferation. Our study presents a novel mechanism of EPO-R regulation in the tumor cells, which may provide information support for NSCLC diagnosis and treatment.

Keywords: EPO-R; Hypoxia; NSCLC

DOI: https://doi.org/10.1186/s12964-019-0458-8

Cancer Sci. 2019 Nov 19.

Lactate-fueled Oxidative Metabolism Drives DNMT1-mediated TAZ Activation.

Tao Huang, Xinglu Zhou, Xike Mao, Chenxi Yu, Zhijian Zhang, Jianke Yang, Yao Zhang, Tianyu Su, Chenchen Chen, Yuxiang Cao, Huijun Wei, Zhihao Wu.

The activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in tumor microenvironment due to metabolic reprogramming are inversely correlated with patient overall survival. Here we investigated the role of lactate in regulation of activity of TAZ and showed glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We demonstrated that the ROS generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT, and thereby inhibited GSK-3β/β-TrCP-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study reveals a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.

Keywords: DNA methyltransferase 1; Lactate; Oxidative Metabolism; TAZ; lung cancer

DOI: https://doi.org/10.1111/cas.14246

J Biochem. 2019 Nov 19. pii: mvz099. [Epub ahead of print]

miR-206 regulates non-small cell lung cancer cell aerobic glycolysis by targeting hexokinase 2.

Ke-Gang Jia, Gang Feng, Yu-Suo Tong, Guang-Zhou Tao, Lian Xu.

Aerobic glycolysis was closely associated with the malignant transformation and prognosis of tumors. miR-206 was found to be downregulated in several cancers. However, whether miR-206 functions in NSCLCs via the process of aerobic glycolysis remains poorly characterized. qRT-PCR was performed to detect miR-206 level in NSCLC cells and tissues. The effect of miR-206 on hexokinase 2 (HK2) expression was examined through miR-206 overexpression or miR-206 knockdown. CCK-8 assay and colony formation assay were carried out to explore the role of miR-206 on cell proliferation and colony formation, respectively. The relationship between miR-206 and HK2 was measured by Dual-luciferase reporter assay. Glucose consumption, lactate production assay and ATP generation were performed in NSCLC cells following miR-206 and HK2 overexpression. We found that miR-206 was downregulated in NSCLC tissues and cells. miR-206 overexpression downregulated the expression of HK2 via targeting HK2 3'UTR in NSCLC cells. In addition, miR-206 decreased the cell viability and colony formation in NSCLC cells. Furthermore, miR-206 reduced glucose uptake, lactate production and ATP generation in NSCLC cells via HK2 repression. In conclusions, these findings suggested that miR-206 regulated NSCLC cell aerobic glycolysis by targeting HK2.

Keywords: glycolysis; hexokinase 2; miR-206; non-small-cell lung cancer; proliferation

DOI: https://doi.org/10.1093/jb/mvz099