Cell Cycle Regulator ING4 Is a Suppressor of Melanoma Angiogenesis That Is Regulated by the Metastasis Suppressor BRMS1

Li, Jun; Li, Gang

doi:10.1158/0008-5472.can-10-3040

Cited by 50 publications

(54 citation statements)

References 32 publications

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“…A variety of factors and genes are involved in breast cancer pathogenesis. The gene ING4 encodes a protein belonging to the inhibitor of growth (ING) family, which are considered to be candidate tumor suppressor genes, playing a pivotal role in apoptosis, cell cycle regulation, DNA damage repair (2)(3)(4)(5) and control of cellular aging (6). Similar to other ING family members, ING4 encodes a 249-amino acid protein containing a highly conserved plant home domain (PHD) finger motif at the C-terminal region, a conserved central region containing the nuclear localization signal (NLS) and a variable N-terminal region (7).…”

Section: Introductionmentioning

confidence: 99%

Effect of the tumor suppressor gene ING4 on the proliferation of MCF-7 human breast cancer cells

Wei

et al. 2012

Oncology Letters

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Abstract. Inhibitor of growth 4 (ING4) is a member of the ING family and acts as a tumor suppressor protein. To investigate the impact of ING4 on breast cancer proliferation, the present study examined the antitumor effects caused by upregulation in the expression of ING4 and its possible mechanism of effect in MCF-7 cells. A plasmid-based expression system encoding the ING4 gene was used to construct a stable cell line and overexpress ING4 in MCF-7 cells. Real-time PCR and western blot analysis were used to detect the mRNA and protein expression levels of ING4, respectively. Cell growth was examined by methylthiazolyltetrazolium (MTT) assay. Cell cycle distribution and cell apoptosis were measured by flow cytometry. The expression of p21, p53 and bax genes were tested by real-time PCR and western blot analysis. The stably transfected cell lines pcDNA3.1(+)/ING4 (with the ING4 gene) and pcDNA3.1(+) (an empty vector) were established. The expression levels of ING4 mRNA and protein in the stable cell line expressing pcDNA3.1(+)/ING4 were significantly higher than those of the two control cell lines. The cell proliferation of stably transfected cells was inhibited, and the inhibitory rate was 62.58±2.93%. Based on the changes in cell cycle distribution in stably transfected cells compared with two control cell lines, a number of cells were blocked in the G0/G1 phase 67.82±3.78% (P<0.05). In addition, the apoptotic rate was significantly higher, at 31.51±3.02% (P<0.05). Real-time PCR revealed that p21 and bax mRNA expression were increased (P<0.01), but the expression of p53 did not change significantly (P>0.05) in the stably transfected cell lines. Western blot analysis results of p21, bax and p53 were in accordance with real-time PCR results. ING4 upregulation may inhibit breast cancer cell proliferation and accelerate the process of apoptosis. It is suggested that ING4 plays a significant role in the suppression of breast cancer progression.

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Section: Introductionmentioning

confidence: 99%

Effect of the tumor suppressor gene ING4 on the proliferation of MCF-7 human breast cancer cells

Wei

et al. 2012

Oncology Letters

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“…Instead, it was noted that the degree of reduction in ING4 expression correlated with the progression from low to high grades of osteosarcoma, according to the Enneking classification system for malignant bone tumors (P=0.002). ING4, a novel tumor suppressor of the ING family, has potential tumor-suppressing effects that are exerted through various signaling pathways, including tumorigenesis, cell cycle regulation, angiogenesis, cell apoptosis, DNA repair, migration and transcriptional regulation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)(39)(40)(41)(42)(43). These functions of ING4, which acts as an oncogene suppressor in numerous tumor types, have been identified repeatedly in vitro and in vivo (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(37)(38)…”

Section: Discussionmentioning

confidence: 99%

“…The upregulation of p21 enhances its binding to cyclin B1, while the compound of cyclin B1/cyclin-dependent kinase 1 is crucial for progression in the cell cycle (18). Conversely, in the p53-defective SaoS-2 cell line, ING4 cannot upregulate p21 or Bax, and is therefore suspected to regulate the cell cycle by directly interacting with p300 or p65 (19). Furthermore, ING4 is able to upregulate Bax while downregulating B cell lymphoma-2 (Bcl-2), thus, decreasing the ratio of Bcl-2/Bax, resulting in cytochrome c release from the mitochondrion and activation of caspase-3.…”

Section: Introductionmentioning

confidence: 99%

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Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

et al. 2016

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Abstract. Osteosarcoma is the most prevalent type of primary malignant bone tumor. Inhibitor of growth 4 (ING4) has been demonstrated to function as a tumor suppressor through multiple pathways, and is its expression is understood to be suppressed or reduced in various malignancies. The present study aimed to investigate the expression of ING4 and to determine its prognostic value in osteosarcoma tissue. Formalin-fixed, paraffin-embedded tissue microarrays were analyzed, and contained 41 osteosarcoma specimens and 11 normal bone tissue specimens with duplicate cores. ING4 expression was evaluated by immunohistochemical staining. The association between ING4 expression in the osteosarcoma and normal bone tissues was analyzed, in addition to the association between ING4 expression and Enneking classification of the osteosarcoma tissues. A significant statistical difference was observed in the ING4 immunohistochemical staining score between the osteosarcoma and normal bone tissues (P<0.001). Furthermore, a significant negative correlation was detected between the ING4 immunohistochemical staining scores and the Enneking classification results of the 41 osteosarcoma tissues (P=0.002). Low expression of ING4 was observed in the osteosarcoma specimens, and this reduced expression of ING4 was negatively correlated with Enneking classification. Thus, the results of the present study indicate that ING4 may serve as a promising prognostic marker in osteosarcoma. IntroductionOsteosarcoma, the most common primary bone malignancy, accounts for ~20% of all bone tumors and ~5% of all pediatric tumors (1). Osteosarcoma has an overwhelming tendency for invasion and early metastasis (2). Although treatment with surgery and neoadjuvant chemotherapy appears to cure 60-70% of cases (3), the 5-year survival rate for patients with recurrent and metastatic osteosarcoma is only 20% (4,5). Research investigating the mechanism of osteosarcoma development has primarily focused on chromosomal abnormalities, genetic alterations of tumor suppressor genes, activation of oncogenes and dysregulation of major signaling pathways. However, the molecular events that lead to the development of osteosarcoma are not yet fully understood.Inhibitor of growth 4 (ING4) functions as a tumor suppressor, thus serving an inhibitory role during the generation and development of various types of tumor, including thyroid (6), gastric (7), lung (8) and breast cancer (9). ING4 physically interacts with and phosphorylates p65, a subunit of nuclear factor-κB (NF-κB), therefore suppressing the activity of NF-κB (10). The inhibition of NF-κB negatively regulates various target genes, including matrix metalloproteinase (MMP)-2, MMP-9, interleukin (IL)-6, IL-8, cyclooxygenase-2 and colony stimulating factor-3. The downregulation of these cytokines inhibits angiogenesis and tumor cell growth (11-15). In RKO colorectal cancer cells, ING4 expression was able to decrease the cell population in the S-phase of the cell cycle in a p53-dependent manner, as well as upregulate p21...

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“…[13][14][15][16] Conversely, ING4-dominant mutant can promote MYC-initiated mouse mammary carcinogenesis. 10 Furthermore, ING4 can suppress the production of IL-6 and IL-8 proangiogenic factors, and the growth of vascular endothelial cells, and consequently inhibit tumor angiogenesis through repressing the activation of nuclear factor-kB (NF-kB) 5,17 and hypoxia inducible factor-1a (HIF-1a). 18,19 Additionally, ING4 can inhibit tumor cell spreading, migration and invasion 15 by interaction with liprin a1 20 and reduced matrix metalloproteinase-2 and 9.…”

Section: Introductionmentioning

confidence: 99%

Enhanced radiosensitivity of non-small-cell lung cancer (NSCLC) by adenovirus-mediated ING4 gene therapy

et al. 2012

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Radiotherapy is the common treatment of choice for locally advanced lung cancer, but the radioresistance of lung cancer remains a significant therapeutic obstacle. We previously demonstrated that adenovirus-mediated inhibitor of growth 4 (ING4) tumor suppressor gene delivery (AdVING4) can chemosensitize human hepatocarcinoma cells to anticancer drug cisplatin (CDDP). However, its radiosensitizing effects in cancer therapy are largely elusive. In the present study, we investigated the therapeutic efficacy of AdVING4 gene therapy combined with ionizing radiotherapy for SPC-A1 human non-small-cell lung cancer (NSCLC) cells in vitro and in vivo in athymic nude mice, and also elucidated its underlying mechanisms. We found that AdVING4 gene therapy plus radiotherapy induced synergistic tumor suppression and apoptosis in in vitro SPC-A1 human NSCLC cells and in vivo SPC-A1 xenografted tumors s.c. implanted in athymic nude mice. Mechanistically, AdVING4 combined with radiation resulted in a substantial upregulation of Bax, Fas, FasL and Cleaved Caspase-3, and downregulation of Bcl-2 in SPC-A1 human NSCLC xenografted tumors. In addition, AdVING4 plus radiation synergistically reduced the tumor vessel CD34 expression and microvessel density (MVD) in vivo. Most importantly, AdVING4 potentially blocked the radiation-induced enhancement of cyclooxygenase-2 and survivin radioresistant factors, and vascular endothelial growth factor and IL-8 proangiogenic factors. The enhanced antitumor effects elicited by AdVING4 plus radiotherapy were closely associated with the cooperative activation of intrinsic and extrinsic apoptotic pathways, and synergistic inhibition of tumor angiogenesis. Thus, our results suggested that AdVING4 combined with radiotherapy may be a feasible and effective strategy for treatment of radioresistant NSCLC and other cancers.

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Cell Cycle Regulator ING4 Is a Suppressor of Melanoma Angiogenesis That Is Regulated by the Metastasis Suppressor BRMS1

Cited by 50 publications

References 32 publications

Effect of the tumor suppressor gene ING4 on the proliferation of MCF-7 human breast cancer cells

Effect of the tumor suppressor gene ING4 on the proliferation of MCF-7 human breast cancer cells

Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

Enhanced radiosensitivity of non-small-cell lung cancer (NSCLC) by adenovirus-mediated ING4 gene therapy

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