MicroRNA-212 suppresses tumor growth of human hepatocellular carcinoma by targeting FOXA1

Dou, Changwei; Wang, Yufeng; Li, Chao; Liu, Zhikui; Jia, Yuli; Li, Qing; Yang, Wei; Yao, Yingmin; Liu, Qingguang; Tu, Kangsheng

doi:10.18632/oncotarget.3916

Cited by 71 publications

(92 citation statements)

References 35 publications

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“…Notably, upregulation of miR-30a-5p also caused a significant decrease in the level of FOXA1 mRNA in HCC cells, suggesting that miR-30a-5p may also indirectly inhibit the transcription of FOXA1, which should be clarified in future studies. Previously, miR-212 was also demonstrated to suppress HCC growth by directly targeting FOXA1 (15). Therefore, other miRs targeting FOXA1 may also serve as tumor suppressors in HCC.…”

Section: Discussionmentioning

confidence: 98%

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MicroRNA-30a-5p suppresses proliferation, invasion and tumor growth of hepatocellular cancer cells via targeting FOXA1

et al. 2017

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Abstract. Deregulation of microRNAs (miRs) has been observed in a variety of types of human cancer. Previously, miR-30a-5p has been demonstrated to exhibit a suppressive role in hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. The present study aimed to elucidate the regulatory mechanism of miR-30a-5p in proliferation and invasion of HCC cells. Quantitative reverse transcription polymerase and western blotting were used to examine mRNA and protein expression of Forkhead box A1 (FOXA1). MTT and Transwell assays were performed to examine proliferation and invasion. Luciferase reporter assay was used to determine the association between miR-30a-5p and FOXA1. The data indicated that miR-30a-5p was significantly downregulated in HCC tissues compared with normal liver tissues. Furthermore, the level of miR-30a-5p was lower in HCC tissues with higher histological grade and advanced tumor stage compared with tissues with lower histological grade and tumor stage. Additionally, restoration of miR-30a-5p expression decreased the proliferation and invasion of HCC HepG2 and SMMC-7721 cells. FOXA1, a novel oncogene in HCC, was further identified as a target of miR-30a-5p. Furthermore, high expression of miR-30a-5p suppressed mRNA and protein expression of FOXA1, while overexpression of FOXA1 reversed the suppressive effect of miR-30a-5p on proliferation and invasion of HepG2 and SMMC-7721 cells. FOXA1 was markedly upregulated in HCC tissues compared with normal liver tissues, and its level was higher in HCC tissues with higher histological grade and advanced tumor stage. In addition, it was found that overexpression of miR-30a-5p significantly suppressed the tumor growth of HCC cells in nude mice. Taken together, the present study supports that miR-30a-5p inhibits the proliferation, invasion, and tumor growth of HCC cells, partly at least, by inhibition of FOXA1 expression, and therefore suggests that miR-30a-5p may serve as a potential candidate for HCC therapy.

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Section: Discussionmentioning

confidence: 98%

“…FOXA1 is essential for estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer (14). Recently, Dou et al (15) reported that miR-212 was able to suppress HCC growth by inhibiting the expression of FOXA1. However, the regulatory mechanism of FOXA1 remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-30a-5p suppresses proliferation, invasion and tumor growth of hepatocellular cancer cells via targeting FOXA1

et al. 2017

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“…miR-212 acts as a tumor suppressor in many cancers 5 6 8. For instance, overexpression of miR-212 has been found to inhibit cell proliferation and cause apoptotic death in hepatocellular carcinoma cells 8.…”

Section: Discussionmentioning

confidence: 99%

“…miR-212 is dysregulated in many human malignancies such as cervical cancer,5 glioblastoma,6 and prostate cancer 7. In several preclinical cancer models, miR-212 shows the ability to suppress solid tumor growth 6 8. It has been documented that miR-212 is involved in B-cell development9 and interleukin-17-producing T helper cell differentiation 10.…”

Section: Introductionmentioning

confidence: 99%

Restoration of microRNA-212 Causes a G0/G1 Cell Cycle Arrest and Apoptosis in Adult T-Cell Leukemia/Lymphoma Cells by Repressing CCND3 Expression

Wang

Guo

Yang

et al. 2017

Journal of Investigative Medicine

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Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR-212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S-phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR-212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL.

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“…HepG2 cells (4x10 6 ) transfected with BCL-3 shRNA or NT shRNA were mixed in 150 µl PBS, and were subcutaneously injected into the flank of each mouse. Tumor growth curves were generated as previously described (18). All animal protocols were approved by the Institutional Animal Care and Use Committee of Xi'an Jiaotong university.…”

Section: Rna Extraction and Reverse Transcription-quantitative Polymementioning

confidence: 99%

BCL-3 promotes the tumor growth of hepatocellular carcinoma by regulating cell proliferation and the cell cycle through cyclin D1

Liu

Yao

et al. 2016

Oncology Reports

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Abstract. Previous studies have demonstrated the aberrant expression and oncogenic role of B-cell CLL/lymphoma-3 (BCL-3) in human malignancies. However, the clinical significance of BCL-3 and its biological function in human hepatocellular carcinoma (HCC) remain unknown. In the present study, the expression levels of BCL-3 protein and mRNA in 90 pairs of HCC and matched non-tumor tissues were analyzed using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). We found that the expression levels of BCL-3 protein and mRNA in HCC tissues were significantly higher than those in the matched tumor-adjacent tissues. In addition, positive expression of BCL-3 was associated with adverse clinicopathological characteristics of the HCC patients including hepatitis B virus (HBV) infection, tumor size, cirrhosis and advanced tumor-node-metastasis (TNM) stage. Moreover, HCC patients with positive expression of BCL-3 had significantly decreased 5-year overall survival and recurrence-free survival. Importantly, BCL-3 expression was an independent prognostic factor for indicating the survival of the HCC patients. Functionally, BCL-3 knockdown markedly inhibited cell viability, proliferation and cell cycle progression in HepG2 cells, while BCL-3 overexpression promoted these cellular processes in Huh7 cells. Accordingly, in vivo experiments indicated that BCL-3 knockdown prominently suppressed the tumor growth of HepG2 cells in nude mice. Mechanistically, we revealed that the expression of cyclin D1 was decreased after BCL-3 knockdown in the HepG2 cells and was increased after BCL-3 overexpression in the Huh7 cells. Cyclin D1 silencing was found to abrogate the functional effects of BCL-3 on cellular processes in Huh7 cells. Taken together, our data suggest that BCL-3 may serve as a promising biomarker and an effective therapeutic target of HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common forms of liver cancer (1) and ranks as the third-leading cause of cancer-related mortality (2). Although numerous therapeutic strategies have been employed to treat this fatal disease, the prognosis of HCC patients remains dismal with a low 5-year survival rate of ~30% (3,4). The unsatisfactory prognosis of HCC largely is attributed to the lack of diagnostic biomarkers and effective therapeutic targets. Therefore, it is of great importance to elucidate the exact mechanisms of the pathogenesis of HCC, and subsequently find promising biomarkers and therapeutic targets of HCC.B-cell CLL/lymphoma-3 (BCL-3) is an atypical member of the IκB family (5) and can bind NF-κB homodimeric complexes of p50 or p52, which switches the transcriptional properties of the homodimers from a repressive to an activating state (6). It was initially identified as a pro-oncogene in cancers of the blood, bone marrow and lymphatic system (7-9). Recently, emerging evidence suggests that BCL-3 also plays promoting roles in the development and progression of various solid tumors (10). The mRNA and protein exp...

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MicroRNA-212 suppresses tumor growth of human hepatocellular carcinoma by targeting FOXA1

Cited by 71 publications

References 35 publications

MicroRNA-30a-5p suppresses proliferation, invasion and tumor growth of hepatocellular cancer cells via targeting FOXA1

MicroRNA-30a-5p suppresses proliferation, invasion and tumor growth of hepatocellular cancer cells via targeting FOXA1

Restoration of microRNA-212 Causes a G0/G1 Cell Cycle Arrest and Apoptosis in Adult T-Cell Leukemia/Lymphoma Cells by Repressing CCND3 Expression

BCL-3 promotes the tumor growth of hepatocellular carcinoma by regulating cell proliferation and the cell cycle through cyclin D1

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