Identification of G protein subunit alpha i2 as a promising therapeutic target of hepatocellular carcinoma

Chen, Min-Bin; Li, Zhifei; Gu, Chengtao; Zheng, Hao; Chen, Yan; Cheng, Long

doi:10.1038/s41419-023-05675-6

Cited by 3 publications

(3 citation statements)

References 52 publications

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Section: Introductionmentioning

confidence: 99%

“…Recent investigations highlight the significant role of Gαi2 protein in the proliferation of cancer cells 26 , 27 . In a study by Chen et al, Gαi2 over-expression was identified as a pivotal factor in promoting the growth of hepatocellular carcinoma (HCC) cells 27 . Silencing or knockout (KO) of Gαi2 led to mitochondrial dysfunction, apoptosis, and growth arrest in HCC cells, impeding HCC xenograft growth in nude mice 27 .…”

Section: Introductionmentioning

confidence: 99%

“…In a study by Chen et al, Gαi2 over-expression was identified as a pivotal factor in promoting the growth of hepatocellular carcinoma (HCC) cells 27 . Silencing or knockout (KO) of Gαi2 led to mitochondrial dysfunction, apoptosis, and growth arrest in HCC cells, impeding HCC xenograft growth in nude mice 27 . Our recent study reported elevated Gαi2 mRNA and protein expression in human gliomas, essential for in vitro and in vivo glioma cell growth 26 .…”

Section: Introductionmentioning

confidence: 99%

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G protein subunit alpha i2's pivotal role in angiogenesis

Bai,

Lu,

Zhang

et al. 2024

Theranostics

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Here we explored the potential role of Gαi2 (G protein subunit alpha i2) in endothelial cell function and angiogenesis. Methods: Genetic methodologies such as shRNA, CRISPR/Cas9, dominant negative mutation, and overexpression were utilized to modify Gαi2 expression or regulate its function. Their effects on endothelial cell functions were assessed in vitro . In vivo , the endothelial-specific Gαi2 shRNA adeno-associated virus (AAV) was utilized to silence Gαi2 expression. The impact of this suppression on retinal angiogenesis in control mice and streptozotocin (STZ)-induced diabetic retinopathy (DR) mice was analyzed. Results: Analysis of single-cell RNA sequencing data revealed Gαi2 ( GNAI2 ) was predominantly expressed in retinal endothelial cells and expression was increased in retinal endothelial cells following oxygen-induced retinopathy (OIR) in mice. Moreover, transcriptome analysis linking Gαi2 to angiogenesis-related processes/pathways, supported by increased Gαi2 expression in experimental OIR mouse retinas, highlighted its possible role in angiogenesis. In various endothelial cell types, shRNA-induced silencing and CRISPR/Cas9-mediated knockout (KO) of Gαi2 resulted in substantial reductions in cell proliferation, migration, invasion, and capillary tube formation. Conversely, Gαi2 over-expression in endothelial cells induced pro-angiogenic activities, enhancing cell proliferation, migration, invasion, and capillary tube formation. Furthermore, our investigation revealed a crucial role of Gαi2 in NFAT (nuclear factor of activated T cells) activation, as evidenced by the down-regulation of NFAT-luciferase reporter activity and pro-angiogenesis NFAT-targeted genes ( Egr3 , CXCR7 , and RND1 ) in Gαi2-silenced or -KO HUVECs, which were up-regulated in Gαi2-overexpressing endothelial cells. Expression of a dominant negative Gαi2 mutation (S48C) also down-regulated NFAT-targeted genes, slowing proliferation, migration, invasion, and capillary tube formation in HUVECs. Importantly, in vivo experiments revealed that endothelial Gαi2 knockdown inhibited retinal angiogenesis in mice, with a concomitant down-regulation of NFAT-targeted genes in mouse retinal tissue. In contrast, Gαi2 over-expression in endothelial cells enhanced retinal angiogenesis in mice. Single-cell RNA sequencing data confirmed increased levels of Gαi2 specifically in retinal endothelial cells of mice with streptozotocin (STZ)-induced diabetic retinopathy (DR). Importantly, endothelial Gαi2 silencing ameliorated retinal pathological angiogenesis in DR mice. Conclusion: Our study highlights a critical role for Gαi2 in NFAT activation, endothelial cell activation and angiogenesis, offering valuable insights into potential therapeutic strategies for modulating these...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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G protein subunit alpha i2's pivotal role in angiogenesis

Bai,

Lu,

Zhang

et al. 2024

Theranostics

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Identification of Gαi3 as a promising molecular oncotarget of pancreatic cancer

Jiang,

Qiao,

Zhu

et al. 2024

Cell Death Dis

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The increasing mortality rate of pancreatic cancer globally necessitates the urgent identification for novel therapeutic targets. This study investigated the expression, functions, and mechanistic insight of G protein inhibitory subunit 3 (Gαi3) in pancreatic cancer. Bioinformatics analyses reveal that Gαi3 is overexpressed in human pancreatic cancer, correlating with poor prognosis, higher tumor grade, and advanced classification. Elevated Gαi3 levels are also confirmed in human pancreatic cancer tissues and primary/immortalized cancer cells. Gαi3 shRNA or knockout (KO) significantly reduced cell viability, proliferation, cell cycle progression, and mobility in primary/immortalized pancreatic cancer cells. Conversely, Gαi3 overexpression enhanced pancreatic cancer cell growth. RNA-sequencing and bioinformatics analyses of Gαi3-depleted cells indicated Gαi3’s role in modulating the Akt-mTOR and PKA-Hippo-YAP pathways. Akt-S6 phosphorylation was decreased in Gαi3-depleted cells, but was increased with Gαi3 overexpression. Additionally, Gαi3 depletion elevated PKA activity and activated the Hippo pathway kinase LATS1/2, leading to YAP/TAZ inactivation, while Gαi3 overexpression exerted the opposite effects. There is an increased binding between Gαi3 promoter and the transcription factor TCF7L2 in pancreatic cancer tissues and cells. Gαi3 expression was significantly decreased following TCF7L2 silencing, but increased with TCF7L2 overexpression. In vivo, intratumoral injection of Gαi3 shRNA-expressing adeno-associated virus significantly inhibited subcutaneous pancreatic cancer xenografts growth in nude mice. A significant growth reduction was also observed in xenografts from Gαi3 knockout pancreatic cancer cells. Akt-mTOR inactivation and increased PKA activity coupled with YAP/TAZ inactivation were also detected in xenograft tumors upon Gαi3 depletion. Furthermore, bioinformatic analysis and multiplex immunohistochemistry (mIHC) staining on pancreatic cancer tissue microarrays showed a reduced proportion of M1-type macrophages and an increase in PD-L1 positive cells in Gαi3-high pancreatic cancer tissues. Collectively, these findings highlight Gαi3’s critical role in promoting pancreatic cancer cell growth, potentially through the modulation of the Akt-mTOR and PKA-Hippo-YAP pathways and its influence on the immune landscape.

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Recent advances in various adeno-associated viruses (AAVs) as gene therapy agents in hepatocellular carcinoma

Hadi,

Qutaiba B. Allela,

Jabari

et al. 2024

Virol J

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Primary liver cancer, which is scientifically referred to as hepatocellular carcinoma (HCC), is a significant concern in the field of global health. It has been demonstrated that conventional chemotherapy, chemo-hormonal therapy, and conformal radiotherapy are ineffective against HCC. New therapeutic approaches are thus urgently required. Identifying single or multiple mutations in genes associated with invasion, metastasis, apoptosis, and growth regulation has resulted in a more comprehensive comprehension of the molecular genetic underpinnings of malignant transformation, tumor advancement, and host interaction. This enhanced comprehension has notably propelled the development of novel therapeutic agents. Therefore, gene therapy (GT) holds great promise for addressing the urgent need for innovative treatments in HCC. However, the complexity of HCC demands precise and effective therapeutic approaches. The adeno-associated virus (AAV) distinctive life cycle and ability to persistently infect dividing and nondividing cells have rendered it an alluring vector. Another appealing characteristic of the wild-type virus is its evident absence of pathogenicity. As a result, AAV, a vector that lacks an envelope and can be modified to transport DNA to specific cells, has garnered considerable interest in the scientific community, particularly in experimental therapeutic strategies that are still in the clinical stage. AAV vectors emerge as promising tools for HCC therapy due to their non-immunogenic nature, efficient cell entry, and prolonged gene expression. While AAV-mediated GT demonstrates promise across diverse diseases, the current absence of ongoing clinical trials targeting HCC underscores untapped potential in this context. Furthermore, gene transfer through hepatic AAV vectors is frequently facilitated by GT research, which has been propelled by several congenital anomalies affecting the liver. Notwithstanding the enthusiasm associated with this notion, recent discoveries that expose the integration of the AAV vector genome at double-strand breaks give rise to apprehensions regarding their enduring safety and effectiveness. This review explores the potential of AAV vectors as versatile tools for targeted GT in HCC. In summation, we encapsulate the multifaceted exploration of AAV vectors in HCC GT, underlining their transformative potential within the landscape of oncology and human health.

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Identification of G protein subunit alpha i2 as a promising therapeutic target of hepatocellular carcinoma

Cited by 3 publications

References 52 publications

G protein subunit alpha i2's pivotal role in angiogenesis

G protein subunit alpha i2's pivotal role in angiogenesis

Identification of Gαi3 as a promising molecular oncotarget of pancreatic cancer

Recent advances in various adeno-associated viruses (AAVs) as gene therapy agents in hepatocellular carcinoma

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