Downregulation of GNA14 in hepatocellular carcinoma indicates an unfavorable prognosis

Tao, Yu; Lu, Shibao; Wenjing, Xie

doi:10.3892/ol.2020.11538

Cited by 3 publications

(4 citation statements)

References 27 publications

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“…However, we observed that GNA14 expression frequently decreased in HCC and GNA14 low expression was an independent predictor for survival outcomes through statistic analysis of HCC samples from local patients. In regards to this, the conclusion was similar to the recent studies ( 19 , 20 ). Moreover, Song et also reported that GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6 ( 20 ).…”

Section: Introductionsupporting

confidence: 92%

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GNA14’s interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway

Sun

et al. 2021

Carcinogenesis

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Gαq subfamily proteins play critical roles in many biological functions including cardiovascular development, angiogenesis and tumourgenesis of melanoma. However, the understanding of G Protein Subunit Alpha 14(GNA14) in diseases, especially in cancers is limited. Here, we revealed that GNA14 was significantly low-expression in human Hepatocellular Carcinoma (HCC) samples. Low GNA14 expression was correlated with aggressive clinicopathological features. Moreover, the overall survival (OS) and disease-free survival (DFS) of high GNA14 expression HCC patients were much better than low GNA14 expression group. Lentivirus-mediated GNA14 knockdown significantly promoted the growth of liver cancer in vitro and in vivo. However, opposing results were observed when GNA14 is up-regulated. Mechanistically, We identified Receptor For Activated C Kinase 1 (RACK1) as a binding partner of GNA14 by coimmunoprecipitation (co-IP) and mass spectrometry (MS). Glutathione-S-transferase (GST) pull-down assay further verified the direct interaction between GNA14 and RACK1. RNA-Seq and loss- and gain-of-function assays also confirmed that GNA14 reduced the activity of both MAPK/JNK and PI3K/AKT signaling pathways through RACK1. GNA14 synergized with U73122 (PLC inhibitor) to enhance this effect. Further studies suggested that GNA14 potentially competed with Protein Kinase C (PKC) to bind with RACK1, consequently reducing the stability of PKC. Moreover, we also showed that GNA14’supression of p-AKT protein level depended on sufficient RACK1 expression. In conclusion, we indicated a different role of GNA14, which acted as a suppressor inhibiting liver cancer progression through MAPK/JNK and PI3K/AKT signaling pathways. Due to this, GNA14 served as a potentially valuable prognostic biomarker for liver cancer.

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Section: Introductionsupporting

confidence: 92%

“…Later studies have reported this. Tao et showed that downregulation of GNA14 in HCC indicated an unfavorable prognosis according to bioinformatic analysis of TCGA data ( 19 ). Song et also reported the same viewpoint.…”

Section: Discussionmentioning

confidence: 99%

GNA14’s interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway

Sun

et al. 2021

Carcinogenesis

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“…The downregulation of GNA14 in hepatocellular carcinoma is significantly associated with tumor grade, clinical stage, and T stage. Knocking out GNA14 in cells can significantly promote cancer growth, and the related mechanism is linked to the activation of signaling pathways such as MAPK/JNK, PI3K/AKT, and Notch1 (Yu et al 2020b ; Song et al 2021 ; Xu et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Establishment and Evaluation of Exosomes-Related Gene Risk Model in Hepatocellular Carcinoma

et al. 2023

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Hepatocellular carcinoma (HCC) is a challenging disease to evaluate in terms of prognosis, requiring close attention to the prognosis of HCC patients. Exosomes have been shown to play an important role in HCC development and have significant potential in managing HCC patient prognosis, as they are detectable in patients’ blood. By using small extracellular vesicular RNA, liquid biopsies can reflect the underlying physiological and pathological status of the originating cells, providing a valuable assessment of human health. No study has explored the diagnostic value of mRNA expression changes in exosomes for liver cancer. The present study investigated establishing a risk prognosis model based on mRNA expression levels in exosomes from blood samples of liver cancer patients and evaluated its diagnostic and prognostic value, providing new targets for liver cancer detection. We obtained mRNA data from HCC patients and normal controls from the TCGA and exoRBase 2.0 databases and established a risk prognostic assessment model using exosomes-related risk genes selected through prognostic analysis and Lasso Cox analysis. The patients were divided into high-risk and low-risk groups based on median risk score values to validate the independence and evaluability of the risk score. The clinical value of the model was further analyzed using a nomograph model, and the efficacy of immunotherapy and cell-origin types of prognostic risk genes were further assessed in the high- and low-risk groups by immune checkpoint and single-cell sequencing. A total of 44 genes were found to be significantly associated with the prognosis of HCC patients. From this group, we selected six genes (CLEC3B, CYP2C9, GNA14, NQO1, NT5DC2, and S100A9) as exosomal risk genes and used them as a basis for the risk prognosis model. The clinical information of HCC patients from the TCGA and ICGC databases demonstrated that the risk prognostic score of the model established in this study was an independent prognostic factor with good robustness. When pathological stage and risk prognostic score were incorporated into the model to predict clinical outcomes, the nomograph model had the best clinical benefit. Furthermore, immune checkpoint assays and single-cell sequencing analysis suggested that exosomal risk genes were derived from different cell types and that immunotherapy in the high-risk groups could be beneficial. Our study demonstrated that the prognostic scoring model based on exosomal mRNA was highly effective. The six genes selected using the scoring model have been previously reported to be associated with the occurrence and development of liver cancer. However, this study is the first to confirm that these related genes existed in the blood exosomes, which could be used for liquid biopsy of patients with liver cancer, thereby avoiding the need for puncture diagnosis. This approach has a high value in clinical application. Through single-cell sequencing, we found that the six genes in the risk model originate from multiple cell types. This finding suggests that the exosomal characteristic molecules secreted by different types of cells in the microenvironment of liver cancer may serve as diagnostic markers.

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“…Activation of GNA14 by ligand treatment or substitution mutations in GNA14 activates the MAPK pathway, an important signaling pathway for cell proliferation, in HepG2, neonatal human melanocytes, and human umbilical vein endothelial cells, respectively [ 9 , 14 ]. On the other hand, studies have found that decreased expression of GNA14 due to DNA hypermethylation are closely related to the progression of hepatocarcinoma [ 15 , 16 ]. Finally, GNA15 has been shown to be significantly overexpressed in gastrointestinal neuroendocrine tumors and pancreatic ductal adenocarcinoma [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor-Promoting Role of GNA14 in Colon Cancer Development

Park,

Lee,

Chin

et al. 2023

Cancers

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Recent studies have shown that mutations in members of the G-protein α family contribute to the onset and progression of cancer. However, the role of GNA14 in CRC remains unknown. In this study, we examined the effect of GNA14 on CRC through genetic approaches in vitro and in vivo. We found that GNA14 knockdown by small interfering RNA (siRNA) inhibited the proliferation of CRC cells SW403 and HT29. Gna14 knockout mice developed normally without obvious abnormalities. However, the number of polyps in the small intestine was significantly reduced in Gna14 knockout mice compared to control mice after mating with ApcMin mice, a representative CRC mouse model. In particular, deletion of the Gna14 inhibited polyp growth, especially in the distal end of the small intestine. Histological examination showed that Gna14 knockout mice suppressed malignant tumor progression due to decreased proliferation and increased apoptosis in polyps compared to controls. In addition, GNA14 knockdown in CRC cells resulted in downregulation of ERK phosphorylation and β-catenin and β-catenin phosphorylation at S675. Similarly, ERK phosphorylation and phospho-β-catenin phosphorylation at S675 were decreased in polyps of Gna14 knockout mice. Collectively, these analyses show that GNA14 may accelerate CRC cell proliferation and malignant tumor progression through ERK and β-catenin pathways.

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Downregulation of GNA14 in hepatocellular carcinoma indicates an unfavorable prognosis

Cited by 3 publications

References 27 publications

GNA14’s interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway

GNA14’s interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway

Establishment and Evaluation of Exosomes-Related Gene Risk Model in Hepatocellular Carcinoma

Tumor-Promoting Role of GNA14 in Colon Cancer Development

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