GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2

Ye, Ying; Song, Yanan; He, Saifei; Zhuang, Juhua; Wang, Guoyu; Xia, Weiya

doi:10.1038/s41417-018-0045-y

Cited by 33 publications

(28 citation statements)

References 40 publications

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“…LOXL2 is a member of the LOX gene family, which encodes a copper-dependent amine oxidase that catalyzes the first step in the formation of crosslinks in collagens and elastin (49,50). It is involved in the progression of tumor progression and metastasis (31,49,(51)(52)(53). Upregulated expression of LOXL2 has been revealed in several types of cancer, including HCC (54).…”

Section: Discussionmentioning

confidence: 99%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial-mesenchymal transition by reducing E-cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose-1, 6-biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail-dependent manner. Overexpression of the point-mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild-type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2-IN-1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF-1α and VEGF in HCC cells, but not in FBP1-knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF-1α/VEGF signaling pathways via the Snail-FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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“…By interrogating GSE37815 data series from GEO database, we found that GINS2 was among the top 5 most DEGs with a log2FC=1.99 and adjusted P value=0.00462. Like TRPM2-AS, we found that GINS2 was considered to be a significant tumor promoter in thyroid cancer [32] lung cancer [33], cervical cancer [40], ovarian cancer [38], breast cancer [34], triple-negative breast cancer [35], and leukemia [39]. Based on these findings, we thus hypothesized that GINS2 might be a tumor promoter in BLCA as well.…”

Section: The Identification Of Genes Of Interest In This Studymentioning

confidence: 73%

“…GINS2 has been preliminarily studied in various human cancers such as that GINS2 enhanced cell proliferation and weakened cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2 expression [32]. GINS2 was upregulated in NSCLC tissues and cell lines, indicating with the poor prognosis outcome of the patients.…”

Section: Discussionmentioning

confidence: 99%

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TRPM2-AS promotes bladder cancer-genesis by targeting miR-22-3p thus releasing GINS2 mRNA

Tian¹,

Guan²,

Su³

et al. 2020

Preprint

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Background: We aimed to study the effects of lncRNA TRPM2-AS in bladder cancer (BLCA) by interacting with its downstream effectors miR-22-3p and GINS2 mRNA.Methods: Online bioinformatic tools were used to identify the key lncRNA, miRNA and mRNA of interest in BLCA. TRPM2-AS, miR-22-3p and GINS2 mRNA expression was measured by qRT-PCR in bladder tissues and selected cell lines. Subcellular localization of TRPM2-AS in T24 and 5637 cell lines was identified using a cellular fractionation method. Luciferase reporter assay, RIP assay and RNA pull-down assay were employed to validate the direct binding relationship between TRPM2-AS, miR-22-3p and GINS2 mRNA. Cell viability, proliferation and apoptosis were measured by a series of cell functional experiments in T24 and 5637 cells.Results: TRPM2-AS was primarily located in cell cytoplasm and significantly up-regulated in BLCA tissues and cell lines. TRPM2-AS knockdown significantly inhibited cell viability and proliferation, but promoted cell apoptosis. miR-22-3p, a significant downstream target of TRPM2-AS, showed a lower expression level in BLCA tissues and cell lines. miR-22-3p inhibition resulted in a significant enhancement of BLCA cancer cell phenotypes. Lastly, GINS2 mRNA was a downstream target of miR-22-3p, and was significantly up-regulated in BLCA. The knockdown of GINS2 led to a significant suppression of BLCA cancer cell phenotypes.Conclusions: TRPM2-AS was a tumor promoter and fulfilling its role through binding to miR-22-3p to increase GINS2 expression. This novel interactome in BLCA might become a new therapy in BLCA.

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“…Since GINS2 mediates the initiation of DNA replication in eukaryotic cells, which is essential for S-phase progression and cell division, GINS2 is more likely to participate in the regulation of cell cycle progression [26]. In addition, previous studies indicated that Cyclin D1 is a key protein in cell cycle regulation [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

GINS2 affects cell viability, cell apoptosis, and cell cycle progression of pancreatic cancer cells via MAPK/ERK pathway

Zhang

et al. 2020

J. Cancer

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Background and Objective: GINS complex subunit 2 (GINS2), a member of the GINS complex, is involved in DNA replication. GINS2 is upregulated in a variety of aggressive tumors, such as leukemia, breast cancer, and cervical cancer. However, the role of GINS2 in pancreatic cancer has still remained elusive. In this study, PANC-1 and BxPC-3 cell lines were chosen to perform experiments in vitro. Additionally, the effects of GINS2 interference on the cell viability, cell apoptosis, cell cycle, and tumor growth in nude mice were analyzed. Methods: We utilized pancreatic cancer cell lines that knocked down GINS2 expression using small interference RNA (siRNA) and evaluated GINS2 expression using Western blot analysis. To explore the function of GINS2 in pancreatic cancer cell lines in vitro, MTT assay and flow cytometry were used. Additionally, we investigated the potential mechanism of GINS2 interference by identifying the MAPK/ERK pathway using Western blotting. Finally, PANC-1 cells with GINS2 knockdown were subcutaneously injected into nude mice to evaluate the effects of GINS2 on tumor growth in vivo. Results: It was unveiled that GINS2 interference inhibited cell viability, induced cell cycle arrest at G1 phase, and enhanced apoptosis of pancreatic cancer cell lines. Western blot assay indicated that GINS2 interference increased the expression level of Bax, while the expression level of Bcl-2 was remarkably decreased. In addition, the expression levels of CDK4, CDK6, and Cyclin D1 were significantly reduced after treatment with GINS2 siRNA. Furthermore, GINS2 interference drastically attenuated the expression levels of MEK, p-MEK, ERK, and pERK , belonging to the MAPK/ERK pathway. The results of an established cancer xenograft model revealed that nude mice transplanted with cells expressing negative control (NC) exhibited larger and heavier tumors, while volume and weight of tumor were remarkably reduced in ones transplanted with cells expressing GINS2 siRNA. Conclusions: GINS2 interference inhibited cell viability, induced cell cycle arrest, and promoted cell apoptosis of pancreatic cancer cell lines via the MAPK/ERK pathway, and our findings may be valuable for treating pancreatic cancer.

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GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2

Cited by 33 publications

References 40 publications

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

TRPM2-AS promotes bladder cancer-genesis by targeting miR-22-3p thus releasing GINS2 mRNA

GINS2 affects cell viability, cell apoptosis, and cell cycle progression of pancreatic cancer cells via MAPK/ERK pathway

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