Novel clinical therapeutics targeting the epithelial to mesenchymal transition

Kothari, Anai N.; Mi, Zhiyong; Zapf, Matthew; Kuo, Paul C.

doi:10.1186/s40169-014-0035-0

Cited by 68 publications

(65 citation statements)

References 128 publications

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“…EMT is closely associated with metastasis, whereas inhibition of EMT could suppress metastasis [52,53]. Targeting the process of EMT appears to be a promising strategy to restrain cancer progression [54,55]. For instance, quite a few approaches have been developed to attenuate the TGF-β signaling, a key player of EMT [54,55].…”

Section: Discussionmentioning

confidence: 99%

“…Targeting the process of EMT appears to be a promising strategy to restrain cancer progression [54,55]. For instance, quite a few approaches have been developed to attenuate the TGF-β signaling, a key player of EMT [54,55]. In the meantime, energy metabolism is also closely associated with EMT, as energy reprogramming during the EMT is necessary for cancer cells to overcome metastatic inefficiency [38,39].…”

Section: Discussionmentioning

confidence: 99%

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An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

Guo¹,

Zhang²,

Chen³

et al. 2015

ABBS

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Epidemiological and experimental studies have suggested that deregulated hepcidin-ferroportin (FPN) signaling is associated with the increased risk of cancers. However, the effects of deregulated hepcidin-FPN signaling on tumor behaviors such as metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2 cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop tumors was also demonstrated in lungs of Hamp1 −/− mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hamp1 −/− mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulating tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded tumor growth and metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and vimentin. Additionally, there was also a reduction of lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the hepcidin-FPN signaling in modulating tumor growth and metastasis, providing new evidence to understand the contribution of this signaling in cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

Guo¹,

Zhang²,

Chen³

et al. 2015

ABBS

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“…It is associated with a number of physiological processes like wound healing, invasion and metastasis [29]. Recent studies have proved that miRNAs play a key role in induction EMT [30, 31]. Here, we have demonstrated the inhibitory effects of miR-196b on EMT in lung cancer cells.…”

Section: Discussionmentioning

confidence: 50%

MicroRNA-196b Inhibits Cell Growth and Metastasis of Lung Cancer Cells by Targeting Runx2

Bai

Lin

Sun

et al. 2017

Cell Physiol Biochem

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Background/Aims: Lung cancer is one of the most common causes of cancer related deaths worldwide. The role of several microRNAs (miRNAs) including miR-196b in different cancers has already been established. The study was aimed to explore the role of miR-196b in lung cancer and its possible underlying mechanism. Methods: Human lung cancer cell line A549 was transfected with miR-196b mimic, miR-196b inhibitor and corresponding controls. Then cell viability, migration, invasion, and apoptosis of A549 lung cancer cells either with overexpression or with suppression of miR-196b were estimated sequentially. Next, dual luciferase activity assay was performed to clarify whether Runx2 was a direct target of miR-196b. Finally, the expressions of main factors associated with epithelial mesenchymal transition (EMT), PI3K/AKT/GSK3β, Smad, and JNK pathways were detected by western blot. Results: MiR-196b expression was significantly decreased in A549, H1650 and H1299 cell lines compared with in WI-38 and HEL-1 cell lines. Overexpression of miR-196b suppressed cell viability, migration, invasion, and induced apoptosis as well as inhibited TGF-β induced EMT process in A549 cells. In addition, Runx2 was a putative target of miR-196b, and Runx2 silence remarkably increased cell apoptosis and abolished the promotive effects of miR-196b suppression on cell viability, migration and invasion. Finally, miR-196b also mediated its action by inactivation of PI3K/AKT/GSK3β, Smad, and JNK pathways by down-regulation of Runx2. Conclusion: MiR-196b functions as a tumor suppressor that inhibited cell growth and metastasis of lung cancer cells by targeting Runx2. These findings provided further evidences for treatment of lung cancer.

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“…A program means a predetermined way, which in our cogitation opposes the plasticity that many animal cells encompass and use to adapt to environmental changes. In other words, the fact that many cells are very plastic and can shift from one form to another, such as the epithelial-mesenchymal transition [41,[49][50][51], seem to disagree with a programmed nature of aging. Aging is programmed in the genome of the fertilized egg, and thus one day we all will die, but in our rumination an aging procedure itself may not be a programmed event, although the difference between the two is difficult to catch, even after it has been repeatedly explained in the literature [42,52,53].…”

Section: The "Catabolic" Vs "Anabolic" Concept May Help Understand Imentioning

confidence: 99%

Is Type 2 Diabetes One of Such Aging Phenomena That Lack an Irreversible Structural Change?

Jia¹,

Chen²,

Jia³

et al. 2015

J Diabetes Metab

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All biological functions should have a structural basis. Any functional change should be due to an alteration in the related structure. If a functional change is irreversible, it should be due to the irreversibility of the structural alteration. For instance, cancer is irreversible because cancer cells have irreversible genetic mutations. However, Type 2 Diabetes (T2D) with Insulin-Resistance (IR) as a central mechanism is irreversible but seems to lack a corresponding irreversible structural change. IR and T2D exhibit many abnormalities that are attributable to altered mitochondria or altered cellular RNAs, proteins, lipids, etc. without genetic mutations involved. These alterations are reversible, because mitochondrial biogenesis can be induced by such as exercise whereas RNAs, proteins and lipids will degrade after some time. Aging is irreversible but many aging manifestations also lack corresponding permanent structural changes, and IR may be one such manifestation. IR affects mainly striated muscles, adipose tissue, brain and liver that are collectively defined herein as the "catabolic cell type" for their low proliferation rates but high metabolism of glucose via oxidation-phosphorylation in mitochondria. In contrast, fast-proliferating cells are defined as the "anabolic cell type" because they are the main cancer origins and often metabolize glucose via glycolysis. Dichotomizing T2D-and cancer-targeted cells and pointing out that the irreversible IR as an aging phenomenon lacks a corresponding irreversible structural change may help understand the differences between, and the mechanisms of, T2D and cancer, although these concepts challenge the "structural-functional relationship" dogma in not only biology but also philosophy. We have been Taught that a Function is Based on a StructureWe as biologists or medical researchers are well educated on structures of various organisms, including the human one. Here, a structure can be something fairly large, such as the anatomy at the macroscopic and microscopic levels, but can also be something very small at the molecular level, such as the sequences and conformations of the DNAs, RNAs, proteins, lipids, starches, etc. Out of this educational background, a concept of structural-functional relationship has been firmly entrenched in our mind. This concept says that a function is based on one sort of architecture or makeup, and any change in a function ultimately can be causally linked to an alteration in the related structure. If the structural alteration is reversed, the function will return to normal as well. For example, based on this rationale, cardiac surgery is performed to fix congenital heart malformation of children. Conversely, irreversible change in a function should be due to an irreversible alteration of a structure.At the molecular level, for a long time it had been thought that proteins were the only executors of cellular functions and all genes had to be expressed ultimately as proteins to be functional, but we now know that many RNAs can al...

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Novel clinical therapeutics targeting the epithelial to mesenchymal transition

Cited by 68 publications

References 128 publications

An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

MicroRNA-196b Inhibits Cell Growth and Metastasis of Lung Cancer Cells by Targeting Runx2

Is Type 2 Diabetes One of Such Aging Phenomena That Lack an Irreversible Structural Change?

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Novel clinical therapeutics targeting the epithelial to mesenchymal transition

Cited by 68 publications

References 128 publications

An important role of the hepcidin&ndash;ferroportin signaling in affecting tumor growth and metastasis

An important role of the hepcidin&ndash;ferroportin signaling in affecting tumor growth and metastasis

MicroRNA-196b Inhibits Cell Growth and Metastasis of Lung Cancer Cells by Targeting Runx2

Is Type 2 Diabetes One of Such Aging Phenomena That Lack an Irreversible Structural Change?

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An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis

An important role of the hepcidin–ferroportin signaling in affecting tumor growth and metastasis