LncRNA RNCR3 Promotes the Progression of HCC by Activating the Akt/GSK3β Signaling Pathway

Objective. To explore the potential biological roles of long noncoding RNA (lncRNA) RNCR3 in human hepatocellular carcinoma (HCC). Methods. First, the expression of RNCR3 was detected by qRT-PCR. Then, in vitro experiments were performed to investigate the effects of RNCR3 on the proliferation, cell cycle, migration, and invasion of HCC cells, while the effects of RNCR3 on HCC tumor growth and metastasis were investigated using in vivo experiments. Finally, western blot was used to study the activation of the Akt/GSK3β signaling pathway. Results. RNCR3 was highly expressed in both HCC tissues and cells, and the expression of RNCR3 was closely related to tumor size, tumor number, TNM stage, and overall survival time. In vitro, RNCR3 served as an oncogene to promote cell proliferation, migration, and invasion, and in vivo, RNCR3 promoted the growth and metastasis of HCC tumors. In terms of mechanism, RNCR3 induced the phosphorylation of Akt (thr308 and ser473) and GSK3β (ser9) but decreased the expression of GSK3β, which activated the Akt/GSK3β signaling pathway. Conclusion. The high expression of lncRNA RNCR3 in HCC can promote the proliferation, migration, invasion, growth, and metastasis of HCC by activating the NF-κB signaling pathway.

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Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the Wnt/β-catenin signaling pathway

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-019-0082-5 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Rui Zhang ◽

Hao-Ming Lin ◽

Ruth Broering ◽

Xiang-de Shi ◽

Xian-huan Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tumor Formation ◽

In Vivo Studies ◽

Qrt Pcr ◽

Subsequent Investigation ◽

Dkk1 Expression ◽

Tumor Number

AbstractDysregulation of dickkopf-related protein 1 (DKK1) expression has been reported in a variety of human cancers. We previously reported that DKK1 was upregulated in hepatocellular carcinoma (HCC). However, the role of DKK1 in HCC remains unclear. This study aimed to investigate the clinical significance and biological functions of DKK1 in HCC. The expression of DKK1 was examined in cirrhotic and HCC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). DKK1 was silenced or overexpressed in HCC cell lines, and in vitro and in vivo studies were performed. Immunohistochemistry revealed that DKK1 was weakly expressed in cirrhotic tissues (8/22, 36.4%) but upregulated in HCC tissues (48/53, 90.6%, cohort 1). Significant upregulation of DKK1 was observed in 57.6% (19/33, cohort 2) of HCC tissues by qRT-PCR, and the expression of DKK1 was associated with tumor size (P = 0.024) and tumor number (P = 0.019). Genetic depletion of DKK1 impaired the proliferation, colony-forming ability, invasion, and tumor formation of HCC cells (HepG2 and HUH-7). Conversely, forced expression of DKK1 increased the proliferation, colony-forming ability, and invasion of HepG2 and HUH-7 cells in vitro and enhanced tumor formation in vivo. Subsequent investigation revealed that the DKK1-mediated proliferation and tumorigenicity of HepG2 and HUH-7 cells is dependent on the Wnt/β-catenin signaling pathway. These findings indicate that DKK1 plays an oncogenic role in HCC by activating the Wnt/β-catenin signaling pathway.

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Novel Long Noncoding RNA miR205HG Functions as an Esophageal Tumor-Suppressive Hedgehog Inhibitor

Cancers ◽

10.3390/cancers13071707 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1707

Author(s):

Jee Hoon Song ◽

Alan H. Tieu ◽

Yulan Cheng ◽

Ke Ma ◽

Venkata S. Akshintala ◽

...

Keyword(s):

Signaling Pathway ◽

Noncoding Rna ◽

Cell Cycle Progression ◽

Esophageal Tumor ◽

Cycle Progression ◽

In Vivo Experiments ◽

Hh Signaling

Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways. However, involvement of lncRNAs in the development of BE and EAC has not been well-studied. The aims of the current study were: (1) to study involvement of the lncRNA, miR205HG, in the development of BE and EAC; (2) to clarify the role of miR205HG in in vitro and in vivo experiments; and (3) to investigate the mechanism of miR205HG involving the Hedgehog (Hh) signaling pathway. These experiments revealed that miR205HG was downregulated in EAC vs. normal esophageal epithelia (NE) as well as in EAC cell lines, and its forced overexpression inhibited EAC cell proliferation and cell cycle progression in vitro. Similarly, overexpression of miR205HG inhibited xenograft tumor growth in mice In vivo. Finally, we show that one mechanism of action of miR205HG involves the Hh signaling pathway: miR205HG and Hh expression levels were inversely correlated in both EAC (r = −0.73) and BE (r = −0.83) tissues, and in vitro studies revealed details of Hh signaling inhibition induced by miR205HG. In conclusion, these findings establish that lncRNA miR205HG functions as a tumor suppressor in the development of BE and EAC, at least in part through its effect on the Hh signaling pathway.

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Overexpression of long noncoding RNA GAS5 suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mToR pathway

10.1101/510511 ◽

2019 ◽

Author(s):

Shuaijun Dong ◽

Xiefu Zhang ◽

Dechun Liu

Keyword(s):

Gastric Cancer ◽

Noncoding Rna ◽

Mtor Pathway ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Qrt Pcr ◽

Non Coding Rnas ◽

Development Of Gastric Cancer

AbstractLong non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. LncRNA GAS5 (GAS5) is identified tumor suppressor involved in several cancers. However, the roles of GAS5 and the mechanisms responsible for its functions in gastric cancer (GC) have not been well undocumented. Herein, the decreased GAS5 and increased miRNA-106a-5p levels were observed in GC and cell lines. GAS5 expression level was significantly inversely correlated with miRNA-106a-5p level in GC tissues. Moreover, luciferase reporter and qRT-PCR assays showed that GAS5 bound to miRNA-106a-5p and negatively regulated its expression in GC cells. Functional experiments showed that GAS5 overexpression suppressed GC cell proliferation, migration, and invasion capabilities and promoted apoptosis, while miRNA-106a-5p overexpression inversed the functional effects induced by GAS5 overexpression. In vivo, GAS5 overexpression inhibited tumor growth by negatively regulating miRNA-106a-5p expression. Mechanistic investigations revealed that GAS5 overexpression inactivating the Akt/mToR pathway by suppressing miRNA-106a-5p expression in vitro and in vivo. Taken together, our findings conclude the GAS5 overexpression suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mToR pathway.

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LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway

Bioscience Reports ◽

10.1042/bsr20180999 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 11

Author(s):

Chunfeng Liu ◽

Lei Ren ◽

Jun Deng ◽

Songping Wang

Keyword(s):

Lung Adenocarcinoma ◽

Cell Lines ◽

Diagnosis And Treatment ◽

Akt Pathway ◽

Migration And Invasion ◽

In Vivo Experiments ◽

Tumor Growth And Metastasis ◽

Phosphoinositide 3 Kinase

Abstract Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion in vitro, and the in vivo experiments illustrated that its knockdown inhibited tumor growth and metastasis. What was more, we discovered that phosphoinositide 3-kinase and AKT (PI3K/AKT) pathway was activated both in LAD tissues and cell lines but inactivated under TP73-AS1 silence. Moreover, the activation of this pathway could rescue the inhibitory effects of TP73-AS1 suppression on LAD cellular processes partially. These data suggested that TP73-AS1 served as an oncogene in LAD partially through activating PI3K/AKT pathway and it could be a potential target for diagnosis and treatment of LAD.

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Long Noncoding RNA FEZF1-AS1 Promotes Osteosarcoma Progression by Regulating the miR-4443/NUPR1 Axis

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504018x15188367859402 ◽

2018 ◽

Vol 26 (9) ◽

pp. 1335-1343 ◽

Cited By ~ 9

Author(s):

Chengwei Zhou ◽

Jianxiang Xu ◽

Jinti Lin ◽

Renjin Lin ◽

Kai Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Migration And Invasion ◽

Normal Tissues ◽

Mg63 Cells ◽

Tumor Growth And Metastasis ◽

And Migration

Long noncoding RNA (lncRNA) FEZF1-AS1 was demonstrated to facilitate cell proliferation and migration in some cancers. However, the functions of FEZF1-AS1 and its molecular mechanism in osteosarcoma remain to be elucidated. In our study, we found that the expression of FEZF1-AS1 was upregulated in osteosarcoma samples and cell lines compared with normal tissues or cells. Besides, we showed that the expression levels of FEZF1-AS1 in osteosarcoma patients were positively correlated with tumor metastasis and TNM stage. Additionally, FEZF1-AS1 knockdown inhibited cell proliferation, migration, and invasion in U2OS and MG63 cells, while upregulation had the opposite effects in vitro. Moreover, FEZF1-AS1 depletion inhibited tumor growth and metastasis in vivo. We found that FEZF1-AS1 sponged miR-4443 to promote NUPR1 expression in U2OS and MG63 cells. Furthermore, knockdown of miR-4443 abrogated FEZF1-AS1 silencing-induced inhibition of cell proliferation, migration, and invasion in osteosarcoma. Finally, we found that restoration of NUPR1 rescued the proliferation, migration, and invasion abilities of FEZF1-AS1-depleted U2OS and MG63 cells. Our study indicated that FEZF1-AS1 could promote osteosarcoma progression by sponging miR-4443 to promote NUPR1 expression. The FEZF1-AS1/miR-4443/NUPR1 axis may act as a novel therapeutic strategy for osteosarcoma treatment.

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Downregulation of long noncoding RNA LINC01419 inhibits cell migration, invasion, and tumor growth and promotes autophagy via inactivation of the PI3K/Akt1/mTOR pathway in gastric cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919874651 ◽

2019 ◽

Vol 11 ◽

pp. 175883591987465 ◽

Cited By ~ 11

Author(s):

Lin-Lin Wang ◽

Lei Zhang ◽

Xiao-Feng Cui

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Tumor Growth ◽

Noncoding Rna ◽

Mtor Pathway ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Tumor Growth And Metastasis

Background: Accumulating evidence has highlighted the crucial role of long noncoding RNAs (lncRNAs) in the tumorigenesis of gastric cancer (GC), which is the most common gastrointestinal malignancy. The present study aimed to identify the capacity of lncRNA LINC01419 (LINC01419) in GC progression, with the potential mechanism explored. Methods: Highly expressed lncRNAs were identified by in silico analysis, with the LINC01419 expression in GC tissues measured using reverse transcription-quantitative PCR (RT-qPCR). The GC cells were subsequently transfected with siRNA against LINC01419 or Rapamycin (the inhibitor of the mTOR pathway), or both, in order to measure cell migration and invasion in vitro as well as tumor growth and metastasis in vivo. Moreover, the expression of PI3K/Akt1/mTOR pathway-associated factors was determined. Results: LINC01419, highly expressed in GC samples of the Gene Expression Omnibus database, was observed to be markedly upregulated in GC tissues. Moreover, LINC01419 silencing, or PI3K/Akt1/mTOR pathway inhibition, exhibited an inhibitory role in GC cell migration and invasion in vitro, coupled with promoted cell autophagy in vitro, and inhibited tumor growth and metastasis in vivo. It was also revealed that LINC01419 silencing blocked the PI3K/Akt1/mTOR pathway, as proved by decreased extents of Akt1 and mTOR phosphorylation. Conclusions: In conclusion, LINC01419 inhibition may suppress GC cell invasion and migration, and promote autophagy via inhibition of the PI3K/Akt1/mTOR pathway. This provides significant theoretical basis and possibilities for further elucidation of the molecular mechanism of GC and finding new molecular-targeted therapeutic regimens.

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Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22041985 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1985

Author(s):

Xiaohe Li ◽

Ling Ma ◽

Kai Huang ◽

Yuli Wei ◽

Shida Long ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Kinase Inhibitor ◽

In Vivo Experiments ◽

Age Related ◽

And Migration ◽

Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

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Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-03985-1 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Jiewei Lin ◽

Zhiwei Xu ◽

Junjie Xie ◽

Xiaxing Deng ◽

Lingxi Jiang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Density Lipoprotein ◽

Human Pancreatic Cancer ◽

Luciferase Reporter ◽

Notch1 Signaling ◽

In Vivo Experiments ◽

Notch1 Signaling Pathway

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

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Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

Experimental Biology and Medicine ◽

10.1177/1535370218762514 ◽

2018 ◽

Vol 243 (7) ◽

pp. 645-654 ◽

Cited By ~ 3

Author(s):

Yi-Quan Yan ◽

Juan Xie ◽

Jing-Fu Wang ◽

Zhao-Feng Shi ◽

Xiang Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Unfavorable Clinical Outcome ◽

Metastasis Models ◽

Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial–mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis.

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HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

International Journal of Molecular Sciences ◽

10.3390/ijms19103153 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3153 ◽

Cited By ~ 6

Author(s):

J. Muñoz-Bello ◽

Leslie Olmedo-Nieva ◽

Leonardo Castro-Muñoz ◽

Joaquín Manzo-Merino ◽

Adriana Contreras-Paredes ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Transcriptional Activation ◽

Target Genes ◽

Promote Cell Proliferation ◽

E6 And E7 ◽

Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

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