The emerging role of RUNX3 in cancer metastasis (Review)

Chen, Feifei; Liu, Xin; Bai, Jing; Pei, Dong‐Sheng; Zheng, Junnian

doi:10.3892/or.2015.4515

Cited by 70 publications

(57 citation statements)

References 105 publications

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“…The mechanisms by which RUNX3 acts in cervical cancer have not been reported. Transcription factor of RUNX3, which is a downstream effector of TGF-β, acts on the TGF-β receptor type II (21) or the downstream protein SMADs, and then promotes the proliferation, apoptosis, angiogenesis, and invasion of tumor cells through TGF-β signal transduction pathway (22)(23)(24), which might explain its wide involvement in tumorigenesis, including that of cervical cancer. In the present study, the recombination plasmid of PCDNA3.1-RUNX3 was constructed and successfully transfected into Hce1 cells.…”

Section: Discussionmentioning

confidence: 99%

The roles of RUNX3 in cervical cancer cells inï¿½vitro

Fan

Deng

et al. 2018

Oncol Lett

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Abstract. RUNX3 serves an important role in development of various types of human cancer. The purpose of the present study was to investigate the potential biological function of RUNX3 in cervical cancer cells. In the present study, a RUNX3 overexpressed model was constructed in Hec1 cells by PCDNA3.1-RUNX3 transfection. Western blot analysis was used to measure RUNX3 expression in cervical cancer cells. Immunofluorescence analysis was performed to examine subcellular localization of RUNX3 in cervical cancer cells. Effects of RUNX3 expression on proliferation, migration and invasion of cervical cancer cells were detected by colony formation assay, wound healing assay and Transwell assay, respectively. Immunofluorescence confirmed the nuclear location of RUNX3 in cervical cancer cell. Result sindicated that upregulation of RUNX3 expression inhibited proliferation, migration and invasion of cervical cancer cells. However, knockdown of RUNX3 expression promoted the proliferation, migration and invasion of cervical cancer cells. Hence, RUNX3 may serve as a tumor suppressor gene in cervical cancer. IntroductionCervical cancer is one of the most common malignancies in women. The incidence is second only to that of breast cancer, which also poses a serious threat to women's health (1). In recent years, one study found that the continuous upgrading of screening methods and the popularity of the human papillomavirus vaccine had caused the incidence of both cervical cancer cases and mortality to decline. Due to the uneven distribution of resources, the incidence is still rising in developing countries, and the trend may affect younger patients (2). As molecular biology research becomes more sophisticated, more and more genes have been found to be involved in the development of cervical cancer. Finding new molecular targets for the prevention and treatment of cervical cancer could have far-reaching implications.The RUNX3 tumor suppressor gene was discovered a few years ago. With RUNX1 and RUNX2, it makes up the transcription factor RUNX family (3). RUNX1 is associated with hematopoietic function (4), and RUNX2 is an important bone formation regulator (5). RUNX3 is located on chromosome 1p36.1 and contains a p1 promoter and p2 promoter (6). Alkaline phosphatase (ALP), a marker of BMP9-induced late osteogenic differentiation was enhanced by the overexpression of RUNX3, whereas it was inhibited by the knockdown of RUNX3 (7). It was first reported to be a tumor suppressor gene in gastric epithelial cells (8), and it was also reported to absent or mutated in a variety of cancers for hemizygous deletions (9), protein mislocalization, epigenetic alterations (10), and histone modifications (11). Suzuki et al (12), initially described the DNA promoter of RUNX3 hypermethylation as a characteristic of breast cancer. Paradoxically, with the discoveries reported by Nevadunsky et al (13) and Lee et al (14), found that RUNX3 took on a growth-stimulating role, which was highly active in ovarian cancer cells, likewise, it even played an o...

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Section: Discussionmentioning

confidence: 99%

The roles of RUNX3 in cervical cancer cells inï¿½vitro

Fan

Deng

et al. 2018

Oncol Lett

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“…Several studies have demonstrated that RUNX3 is a downstream effector of TGF-β and Notch signaling pathways, and plays critical roles in regulating cell functions, such as angiogenesis, cell migration and apoptosis (14,15,17,25). Our results showed that TGF-β and Notch signaling were activated during the hypoxia-induced EndMT of HCMECs.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately a decade ago RUNX3 was claimed to be a tumor suppressor that inhibited the expression of vascular endothelial growth factor (VEGF) and reduced the angiogenesis, growth, and metastasis of human gastric cancer (13). RUNX3 is a direct target gene of Notch in human endothelial cells and a downstream effector of the TGF-β signaling pathway, and plays a critical role in angiogenesis, cell migration and invasion (14,15). Recent studies suggest that RUNX3 knockdown enhances endothelial progenitor cell (EPC) function and that miR-130a regulates EPC autophagy through RUNX3 (16,17).…”

Section: Introductionmentioning

confidence: 99%

RUNX3 modulates hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial cells

Liu

Zhang

et al. 2017

International Journal of Molecular Medicine

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Endothelial-mesenchymal transition (EndMT) is an essential mechanism in the cardiovascular system, for both cardiovascular development and cardiovascular diseases (CVDs). Recent studies indicate that runt-related transcriprunt-related transcription factor 3 (RUNX3) contributes to EndMT and endothelial cell dysfunction. However, the underlying molecular mechanism remains unknown. The present study was designed to investigate the role of RUNX3 in EndMT and endothelial cell function, and to elucidate the underlying molecular mechanism. Human cardiac microvascular endothelial cells (HCMECs) were incubated in strictly controlled hypoxic conditions (1% O2). HCMECs were cultured under normoxic conditions (21% O2), and then moved to a strictly controlled hypoxic environment (1% O2). Under this hypoxic condition, the cells were transfected with the lentiviral vector containing RUNX3 or an empty lentiviral vector for 8 h. After the cells were cultured under hypoxic conditions for 4 days, CD31 and α-smooth muscle actin colocalization were assessed by immunofluorescence microscopy. Transwell migration and tube formation assays were used to examine the migration and angiogenesis ability. RT-qPCR and western blotting were used to determine the expression of molecules involved in EndMT. Hypoxia induced the transition of HCMECs to mesenchymal cells and markedly promoted tube formation and cell migration. Transforming growth factor-β (TGF-β) and Notch signaling were activated during the hypoxia-induced EndMT of HCMECs. RUNX3 knockdown attenuated EndMT of HCMECs, promoted angiogenic phenotype, and reduced endothelial cell migration. In conclusion, our results showed that RUNX3 knockdown attenuated hypoxia-induced EndMT and reversed endothelial cell functions. RUNX3 is a common downstream target of TGF-β and Notch signaling, and may be a novel therapeutic target for treating CVD mediated by EndMT.

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“…Three members of the runt‐related transcription factor (RUNX) family genes, RUNX1 , RUNX2 , and RUNX3 transcription factors, are known as important developmental regulators in the inception and progression of a variety of human cancers . RUNX3 is a tumor suppressor gene that participates in the regulation of cell proliferation and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…Three members of the runt-related transcription factor (RUNX) family genes, RUNX1, RUNX2, and RUNX3 transcription factors, are known as important developmental regulators in the inception and progression of a variety of human cancers. 4 RUNX3 is a tumor suppressor gene that participates in the regulation of cell proliferation and apoptosis. It has been reported that the changes in RUNX3 protein levels or functions are associated with various epithelial cancers, Abbreviations: LSCC, Laryngeal squamous cell carcinoma; RUNX3, Runt-related transcription factor 3; DNMTs, DNA (cytosine-5-)-methyltransferases; miRNA, microRNA; 3′-UTR, 3′ untranslated region; FBS, fetal bovine serum including LSCC.…”

Section: Introductionmentioning

confidence: 99%

RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR‐148a‐3p/DNMT1 axis

et al. 2016

Cell Biochemistry & Function

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Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. Runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to related to lymph node metastasis and the development of LSCC. However, the biological roles and potential mechanisms RUNX3 expression was not well understood. In this study, we reported that the RUNX3 was significantly downregulated and highly methylated in LSCC compared with their matched normal. The enforced expression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. We identified that RUNX3 was regulated by miR-148a-3p and found that the expression level of miR-148-3p was significantly decreased and positively related with the expression of RUNX3 in LSCC. We also identified that DNA methyltransferase enzyme DNA (cytosine-5-)-methyltransferase 1 (DNMT1) was targeted by miR-148a-3p in LSCC. The knockdown of DNMT1 promoted the expression of RUNX3 and inhibited migration, invasion, and proliferation in LSCC cells. In summary, our study demonstrated that miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC. LSCC is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. In this study, we reported that RUNX3, an important tumor suppressor, was significantly downregulated and highly methylated in LSCC compared with their matched normal. The overexpression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. Moreover, RUNX3 was regulated by miR-148a-3p, which targeted DNA methyltransferase enzyme DNMT1 in LSCC cells. Therefore, miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC.

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The emerging role of RUNX3 in cancer metastasis (Review)

Cited by 70 publications

References 105 publications

The roles of RUNX3 in cervical cancer cells inï¿½vitro

The roles of RUNX3 in cervical cancer cells inï¿½vitro

RUNX3 modulates hypoxia-induced endothelial-to-mesenchymal transition of human cardiac microvascular endothelial cells

RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR‐148a‐3p/DNMT1 axis

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