Role of WWOX and NF-κB in lung cancer progression

Chen, Szu-Jung; Huang, Shu-Ching; Chang, Nan‐Shan

doi:10.1186/2213-0802-1-15

Cited by 21 publications

(16 citation statements)

References 101 publications

(174 reference statements)

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“…After lung adenocarcinoma A549 cells were co-cultured with macrophages, NF-κB was activated in lung adenocarcinoma A549 cells and tumor cell proliferation and invasion abilities were significantly enhanced. The observed phenotype was consistent with previous research (26,27). The CaSR promoter region, which contains a functional response element κB, upregulates the NF-κB signaling pathway, activates CaSR, and participates in pathological processes, such as inflammatory bone resorption (28)(29)(30).…”

Section: Discussionsupporting

confidence: 92%

CaSR Induces Osteoclast Differentiation and Promotes Bone Metastasis in Lung Adenocarcinoma

et al. 2020

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Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma. Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-κB. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-κB expression identified a regulatory relationship between NF-κB and CaSR. Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-κB and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down. Liu et al. CaSR Osteoclast Differentiation Bone Metastasis Conclusions: CaSR can positively regulate NF-κB and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.

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Section: Discussionsupporting

confidence: 92%

CaSR Induces Osteoclast Differentiation and Promotes Bone Metastasis in Lung Adenocarcinoma

et al. 2020

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“…Subsequent exposure of UV-treated cells to cold shock enhances accumulation of these proteins in the nucleus. NF-κB/p65 is a downstream effector of the TNF signaling, which blocks TNF-mediated cell death and thereby provides cancer survival [ 31 , 32 ]. Hyal-2 acts as an alternative receptor for TGF-β1 and a binding protein for WWOX [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures

et al. 2015

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When COS7 fibroblasts and other cells were exposed to UVC irradiation and cold shock at 4°C for 5 min, rapid upregulation and nuclear accumulation of NOS2, p53, WWOX, and TRAF2 occurred in 10–30 min. By time-lapse microscopy, an enlarging gas bubble containing nitric oxide (NO) was formed in the nucleus in each cell that finally popped out to cause “bubbling death”. Bubbling occurred effectively at 4 and 22°C, whereas DNA fragmentation was markedly blocked at 4°C. When temperature was increased to 37°C, bubbling was retarded and DNA fragmentation occurred in 1 hr, suggesting that bubbling death is switched to apoptosis with increasing temperatures. Bubbling occurred prior to nuclear uptake of propidium iodide and DAPI stains. Arginine analog Nω-LAME inhibited NO synthase NOS2 and significantly suppressed the bubbling death. Unlike apoptosis, there were no caspase activation and flip-over of membrane phosphatidylserine (PS) during bubbling death. Bubbling death was significantly retarded in Wwox knockout MEF cells, as well as in cells overexpressing TRAF2 and dominant-negative p53. Together, UV/cold shock induces bubbling death at 4°C and the event is switched to apoptosis at 37°C. Presumably, proapoptotic WWOX and p53 block the protective TRAF2 to execute the bubbling death.

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“…We have demonstrated that both WWOX and p53 function in a synergistic manner in causing apoptosis under various stress conditions. [8][9][10][11][12] Our supporting evidence revealed that NO, nitric oxide synthase 2 (NOS2), p53 and WWOX enhance in the bubbling death, whereas antiapoptotic TRAF2 blocks the cell death. 12 Importantly, nuclear accumulation of p53 and WWOX is needed to activate NOS2 to induce formation of NO.…”

Section: Wwox In Bubbling Deathmentioning

confidence: 93%

“…1,[8][9][10][11][12][13] In our most recent study, we have reported temperature-regulated ''bubbling death'' and its transition with apoptosis. 12 Bubbling death is defined as ''formation of a bubble from the nucleus and release of this swelling bubble to the cell surface that causes cell death''.…”

Section: Wwox In Bubbling Deathmentioning

confidence: 99%

Introduction to a Thematic Issue for WWOX

Chang

2015

Exp Biol Med (Maywood)

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Since its discovery in 2000, WW domain-containing oxidoreductase (WWOX, FOR or WOX1) has been considered as a tumor suppressor protein. Global research focus has been aimed mainly toward this direction. In this thematic issue, updated information has been collected regarding the structure, function and signaling of WWOX, along with its critical role as a tumor suppressor and participation in metabolism, neurodegeneration, ataxia, epilepsy, neural disorders, neuronal damages, and interactions with oncogenic viruses. WWOX is not a driver of cancer initiation. Chromosomal alterations in the WWOX gene enhance cancer progression. Importantly, a homozygous nonsense mutation of WWOX gene in humans leads to neural pathologies and early death, rather than spontaneous cancer development. These findings suggest new physiological functions of WWOX in metabolism and neural diseases, and these areas require further investigation.

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Role of WWOX and NF-κB in lung cancer progression

Cited by 21 publications

References 101 publications

CaSR Induces Osteoclast Differentiation and Promotes Bone Metastasis in Lung Adenocarcinoma

CaSR Induces Osteoclast Differentiation and Promotes Bone Metastasis in Lung Adenocarcinoma

UV irradiation/cold shock-mediated apoptosis is switched to bubbling cell death at low temperatures

Introduction to a Thematic Issue for WWOX

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