CD73 on B16F10 melanoma cells in CD73-deficient mice promotes tumor growth, angiogenesis, neovascularization, macrophage infiltration and metastasis
Patrycja KoszałkaMonika GołuńskaMarcin StanisławowskiA UrbánGrzegorz StasiłojćMarceli MajewskiPiotr WierzbickiAndrzej C. SkładanowskiJacek Bigda
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In this review, we present a literature survey of angiogenesis in melanoma. Progression in melanoma is supposed to be associated with an angiogenic response. Several histological studies have shown an increase of vascular structures in malignant melanoma, which is not the case in common naevocellular naevi. Neovascularization can be caused by several angiogenic factors: the most important of those produced in melanoma are described. Proteases such as urokinase plasminogen activator and metalloproteinases are important for the migration for both endothelial cells and tumour cells. Possible effects of these factors in melanoma cells are discussed. Finally, inhibition of angiogenesis and its potential role in melanoma therapy are considered.
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Lung cancer is the leading cause of cancer-related mortality worldwide, characterized by uncontrolled proliferation and metastasis of lung cancer cells. Tumor angiogenesis plays a key role in proliferation and metastasis in cancers, and is an essential component in microenvironment. It has been reported that long non-coding RNA FBXL19-AS1 plays an oncogenic role in colorectal cancer. However, the molecular mechanism of FBXL19-AS1 in lung cancer has not been fully elucidated. In the present study, we found that FBXL19-AS1 expression was up-regulated in lung cancer tissues and cell lines. FBXL19-AS1 knockdown inhibited cell proliferation, migration, invasion, and angiogenesis in lung cancer cells. Molecular mechanism exploration uncovered that FBXL19-AS1 acted as a molecular sponge of miR-431-5p and that RAF1 was a downstream target of miR-431-5p in lung cancer. Moreover, there was a negative association between miR-431-5p expression and FBXL19-AS1 or RAF1 expression in tumor tissues. Through rescue experiments, we discovered that overexpression of RAF1 partially rescued FBXL19-AS1 knockdown-mediated inhibition of angiogenesis and progression in lung cancer. Together, these results indicated that FBXL19-AS1 was involved in progression and angiogenesis in lung cancer by targeting miR-431-5p/RAF1 axis, which provided a new insight into the therapeutic strategies of lung cancer.
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Long non-coding small nucleolar RNA host gene 7 (lncRNA SNHG7) was verified to act as an onco-gene in human cancers. Nevertheless, the role of SNHG7 in malignant melanoma remains elusive. The present study showed an increase of SNHG7 expression in malignant melanoma tissues and cell lines. Besides, SNHG7 knockdown inhibited proliferation and migration in malignant melanoma cells. Bioinformatics analysis demonstrated that SNHG7 functions as a molecular sponge for miR-9 in biological behavior of melanoma cells. And miR-9 could inhibit the expression of PI3KR3 by binding with the 3'-UTR. Furthermore, PI3KR3, pAKT, cyclin D1 and Girdin expression was down-regulated after SNHG7 knockdown by siRNA. In addition, SNHG7 knockdown decreased xenograft growth in vivo. Taken together, this research demonstrated that SNHG7 was an oncogene in malignant melanoma, providing a novel insight for the pathogenesis and new potential therapeutic target for malignant melanoma.
Malignant Transformation
Small nucleolar RNA
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Although recent studies have revealed TAR (trans-activating response region) DNA binding protein (TDP-43) as a potential therapeutic target for cancers, its role and clinical association with melanoma have not been explored.To identify the role and function of TDP-43 during melanoma pathogenesis.Firstly, the relationship between TDP-43 expression and patient survival was explored. Then TDP-43 expression level in melanoma tissue and different melanoma cell lines was measured. After silencing TDP-43 expression in melanoma cells, the impacts of TDP-43 on cellular proliferation, metastasis, glucose uptake, and glucose transporters levels were studied. In the end, effect of TDP-43 depletion on tumorigenicity of melanoma cells was tested in vivo.Our results showed that TDP-43 was overexpressed in melanoma paraffin samples compared with that in nevi tissues. The high expression level of TDP-43 was associated with poor patient survival. By silencing TDP-43, we saw significant inhibition of cell proliferation and metastasis in A375 and WM451 cells. TDP-43 knockdown could suppress glucose transporter type-4 (GLUT4) expression and reduce glucose uptake. And downregulation of GLUT4 in melanoma cells induced inhibition of cell proliferation and metastasis. TDP-43 knockdown significantly slowed down tumor growth and decreased GLUT4 expression in vivo.TDP-43 is a novel oncogene in melanoma and regulates melanoma proliferation and metastasis potentially through modulation of glucose metabolism.
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It is known that the growth and metastasis of malignant tumors depends on neovascularization. It has also been suggested that the degree of tumor angiogenesis is related to clinical outcome in several tumor types. This is true for gastric carcinoma, where tumor angiogenesis is closely correlated with prognosis and hematogenous metastasis. Several types of angiogenic factors have been investigated in gastric cancer. In the current review, the correlation between angiogenesis / angiogenic factor expression and prognosis in gastric cancer is discussed. Moreover, the potential clinical applications of antivascular, anti-angiogenic and angiostatic agents for the treatment of gastric carcinoma are summarized.
Gastric carcinoma
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Angiogenesis plays a crucial role in tumor growth and metastases. It is becoming clear that many malignant tumors generate both stimulators and inhibitors of neovascularization, and a net balance between these position and negative regulators decides finally tumoral angiogenesis activation. Measuring the levels of some main stimulators and/or inhibitors of angiogenesis in solid tumors or in the serum or urine may reflect the information about tumor angiogenesis activation, further provides new and sensitive markers for tumor progression, metastasis and prognosis.
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Abstract We have previously demonstrated that overexpression of T lymphoma invasion and metastasis 1 ( Tiam1 ) is correlated with poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we tried to further investigate the potential roles of Tiam1 in the progression of HCC in a larger set of samples. By detecting Tiam1 expression in 213 HCC patients, we observed that Tiam1 had a higher probability of being overexpressed in HCC patients with metastasis than those without metastasis (68.3% vs . 52.7%, p = 0.036). In addition, the cell line with high metastatic potential expressed more Tiam1 than did the cell line with low metastatic potential. Overexpression of Tiam1 was suggested to be significantly correlated with HCC metastasis. We stably upregulated Tiam1 expression in MHCC97L as well as knocked down Tiam1 expression in HCCLM6. We also investigated the effects of Tiam1 overexpression and knockdown on HCC cells proliferation, migration and invasion in vitro and on tumorigenicity and metastasis in vivo . Overexpression of Tiam1 increased proliferation, migration and invasion of MHCC97L cells, while knockdown of Tiam1 in HCCLM6 cells resulted in the reverse. In vivo functional studies showed upregulation of Tiam1 expression led to an enhancement of tumorigenicity and metastatic potential in mice. However, knockdown of Tiam1 expression exhibited nearly 2.2‐fold retardation in tumor growth and great inhibition on tumor metastases. Our results indicate that Tiam1 , as a metastasis‐related gene, may contribute to HCC invasion and metastasis, and consequently, it may be a useful biomarker for therapeutic strategy and control in HCC treatment.
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Exosome
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Melanoma is the most malignant skin cancer, which account for most of skin-cancer-related deaths. Long noncoding RNA (lncRNA) is a class of noncoding RNAs with crucial roles in many cancers. However, the roles of lncRNAs in melanoma have not been well studied. In the present study, using public available data and clinical tissues samples, we found that lncRNA ILF3-AS1 is up-regulated in melanoma tissues and cell lines, and correlated with poor prognosis of melanoma patients. Functional experiments showed that knockdown of ILF3-AS1 inhibits melanoma cell proliferation, migration, and invasion. Mechanistically, we found that ILF3-AS1 interacts with EZH2, promotes the binding of EZH2 to the miR-200b/a/429 promoter, and represses miR-200b/a/429 expression. The expression of ILF3-AS1 is negatively correlated with that of miR-200b/a/429 in melanoma tissues. Moreover, inhibition of miR-200b/a/429 abrogates the biological roles of ILF3-AS1 knockdown on melanoma cell proliferation, migration, and invasion. In conclusion, these results demonstrate that melanoma-upregulated lncRNA ILF3-AS1 promotes cell proliferation, migration, and invasion via negatively regulating miR-200b/a/429, and imply that ILF3-AS1 may be a potential prognostic biomarker and therapeutic target for melanoma.
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// Jinhua Wang 1 , Wei Hua 2 , Sharon K. Huang 1 , Kun Fan 2 , Ling Takeshima 1 , Ying Mao 2 , Dave S.B. Hoon 1 1 Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center, Santa Monica, CA 2 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China Correspondence to: Dave S.B. Hoon, e-mail: hoond@jwci.org Keywords: RASSF8, P53, melanoma, methylation, P65 Received: July 14, 2015 Accepted: August 03, 2015 Published: August 17, 2015 ABSTRACT Our group previously demonstrated that the RASSF1 gene has a significant tumor suppressor role in cutaneous melanoma. The RASSF8 gene is a member of the N-terminal RASSF gene family. Previously, we identified RASSF8 (HOJ1, NCBI Gene ID:11228) expression in cutaneous melanoma; however the functional role of RASSF8 in melanoma is not known. RASSF8 expression was assessed in melanoma cell lines and tumors of different AJCC stages. Results indicated that RASSF8 expression was low in metastatic melanoma lines and decreased with melanoma progression. We then explored the mechanism of RASSF8 downregulation in melanoma by assessing methylation of RASSF8 and demonstrated that methylation of RASSF8 gene promoter was higher in advanced than in early stages melanomas. Functional activity of RASSF8 in melanoma lines by knockdown and overexpression of RASSF8 demonstrated that RASSF8 expression significantly inhibited cell growth, cell migration and invasion, whereas knockdown of RASSF8 expression significantly increased cell growth, cell migration and invasion of melanoma cells by increasing expression of P65 and its downstream target IL-6. Moreover RASSF8 was found to induce apoptosis in melanoma cells by activating the P53-P21 pathway, and also in vivo studies demonstrated that inhibiting RASSF8 increases the tumorigenic properties of human melanoma xenografts. These results suggest that RASSF8 plays a significant role in suppressing the progression of cutaneous melanoma.
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