Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis

Lee, Young-Kyoung; Kwon, So Mee; Lee, Eun-beom; Kim, Gyeong-Hyeon; Min, Seungwook; Hong, Sunmi; Wang, Hee-Jung; Lee, Dong Min; Choi, Kyeong Sook; Park, Tae Jun; Yoon, Gyesoon

doi:10.3390/cancers12092632

Cited by 18 publications

(22 citation statements)

References 45 publications

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“…Moreover, a distinct pool of STAT3 resides in the mitochondria and is responsible for the control of ETC, modulation of ROS production, Ras transformation, cellular growth, and protection from ischemia/reperfusion injuries through the regulation of the mitochondrial permeability transition pore (MPTP) [ 77 ]. Very recently, Lee et al elucidated a role in hepatoma cell invasiveness of ROS-induced STAT3 activation, which in turn promoted Nrf2 transcription and syntaxin 12 expression [ 78 ].…”

Section: Mitochondrial Ros Involvement In Cancermentioning

confidence: 99%

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Brillo

Chieregato

Leanza

et al. 2021

Life

106

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Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

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Section: Mitochondrial Ros Involvement In Cancermentioning

confidence: 99%

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Brillo

Chieregato

Leanza

et al. 2021

Life

106

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“…To monitor mitochondrial respiratory activity, OCR was measured using Seahorse XF24 analyzer (Seahorse Bioscience Inc., MA) as described in the previous report [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness

et al. 2021

Self Cite

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Deregulated mitochondrial energetics is a metabolic hallmark of cancer cells. However, the causative mechanism of the bioenergetic deregulation is not clear. In this study, we show that somatic copy number alteration (SCNA) of mitoribosomal protein (MRP) genes is a key mechanism of bioenergetic deregulation in hepatocellular carcinoma (HCC). Association analysis between the genomic and transcriptomic profiles of 82 MRPs using The Cancer Genome Atlas-Liver HCC database identified eight key SCNA-dependent MRPs: MRPS31, MRPL10, MRPL21, MRPL15, MRPL13, MRPL55, and DAP3. MRPS31 was the only downregulated MRP harboring a DNA copy number (DCN) loss. MRPS31 loss was associated specifically with the DCN losses of many genes on chromosome 13q. Survival analysis revealed a unique dependency of HCC on the MRPS31 deficiency, showing poor clinical outcome. Subclass prediction analysis using several public classifiers indicated that MRPS31 loss is linked to aggressive HCC phenotypes. By employing hepatoma cell lines with SCNA-dependent MRPS31 expression (JHH5, HepG2, Hep3B, and SNU449), we demonstrated that MRPS31 deficiency is the key mechanism, disturbing the whole mitoribosome assembly. MRPS31 suppression enhanced hepatoma cell invasiveness by augmenting MMP7 and COL1A1 expression. Unlike the action of MMP7 on extracellular matrix destruction, COL1A1 modulated invasiveness via the ZEB1-mediated epithelial-to-mesenchymal transition. Finally, MRPS31 expression further stratified the high COL1A1/DDR1-expressing HCC groups into high and low overall survival, indicating that MRPS31 loss is a promising prognostic marker. Significance Our results provide new mechanistic insight for mitochondrial deregulation in HCC and present MRPS31 as a novel biomarker of HCC malignancy.

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“…Another group led by Yoon reported that Nrf1 acts as one of the most responsive genes when the mitochondrial respiratory chain is damaged (70,71). These putative effects of Nrf1 prompt us to gain insights into its redox regulation for mitochondrial homeostasis, because this organelle is a main resource of intracellular ROS production.…”

Section: Nrf1 Serves As An Indispensable Redox-determining Factor In ...mentioning

confidence: 99%

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks

Feng

Wang

et al. 2022

Preprint

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To defend a vast variety of challenges in the oxygenated environments, all life forms have been evolutionally established a set of antioxidant, detoxification and cytoprotective systems during natural selection and adaptive survival, in order to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1-/- cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1-/- resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called aPalNRF1 and GABPNRF2. In addition to antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1-/- cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-kB, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.

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Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis

Cited by 18 publications

References 45 publications

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

MRPS31 loss is a key driver of mitochondrial deregulation and hepatocellular carcinoma aggressiveness

Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks

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