Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges

Paskeh, Mahshid Deldar Abad; Ghadyani, Fatemeh; Hashemi, Mehrdad; Abbaspour, Alireza; Zabolian, Amirhossein; Javanshir, Salar; Razzazan, Mehrnaz; Mirzaei, Sepideh; Entezari, Maliheh; Goharrizi, Mohammad Ali Shekhi Beig; Salimimoghadam, Shokooh; Aref, Amir Reza; Kalbasi, Alireza; Rajabi, Romina; Rashidi, Mohsen; Taheriazam, Afshin; Sethi, Gautam

doi:10.1016/j.phrs.2022.106553

Cited by 70 publications

(24 citation statements)

References 374 publications

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“…These pathways are closely related to malignancy in CNIH4. For instance, PI3K‐AKT and mTOR signaling pathways are critically involved in tumor invasion and metastasis 12–15 . The PI3K‐AKT pathway mediates the development and differentiation of both T and B cell populations 16,17 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

Wang,

Wang

et al. 2023

Cancer Medicine

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BackgroundCornichon homolog 4 (CNIH4) belongs to the CNIH family. It functions as an oncogene in many tumors. However, CNIH4's significance in the immune landscape and its predictive potential in cervical cancer (CESC) is unexplored.MethodsCNIH4 levels and its effect on the survival of patients with CESC were evaluated using data retrieved from The Cancer Genome Atlas (TCGA). The oncogenic effect of CNIH4 in CESC was determined using small interfering RNA‐mediated transfected cell lines and tumorigenesis experiments in animal models.ResultsHigher expression of CNIH4 was found in advanced tumor and pathological stages, as well as lymph node metastasis. CNIH4 expression correlated positively with the infiltration of macrophages M2 and resting dendritic cells into the affected tissue. Additionally, functional enrichment of RNA‐sequencing of CNIH4‐knocked down CESC cell lines showed the association of CNIH4 to the PI3K‐Akt signaling pathway. Single‐sample gene set enrichment analysis highlighted several immune pathways that were elevated in the CESC samples with enhanced levels of CNIH4, including Type‐I and Type‐II IFN‐response pathways. The impact of CNIH4 on drug sensitivity was further assessed using the GDSC database. As CNIH4 is linked to the immune landscape in CESC, this study determined a four‐gene risk prediction signature utilizing CNIH4‐related immunomodulators. The risk score quantified from the prediction signature was an independent predictive indicator in CESC. Receiver operating characteristic curve analysis verified the good predictive ability of the four‐gene signature in TCGA‐CESC cohort. Thus, the CNIH4‐related model showed potential as an auxiliary TNM staging system tool.ConclusionCNIH4 may be an effective predictive biomarker for patients with cervical cancer, thus providing new ideas and research directions for CESC.

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

Wang,

Wang

et al. 2023

Cancer Medicine

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“…Recently, many groups have demonstrated a vital role for the PI3K/AKT pathway in autoimmune diseases and implicated its suppression in the progression of liver IRI. [40][41][42] The PI3K pathway includes AKT and mTOR signaling, which are activated by tyrosine kinase receptor dimerization in response to growth factor binding. 43 This pathway represents an important regulatory component for both pro-inflammatory cytokines and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Pan,

Yu,

Song

et al. 2024

The FASEB Journal

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Liver transplantation (LT) is the only effective method to treat end‐stage liver disease. Hepatic ischemia‐reperfusion injury (IRI) continues to limit the prognosis of patients receiving LT. Histone deacetylase 6 (HDAC6) is a unique HDAC member involved in inflammation and apoptosis. However, its role and mechanism in hepatic IRI have not yet been reported. We examined HDAC6 levels in liver tissue from LT patients, mice challenged with liver IRI, and hepatocytes subjected to hypoxia/reoxygenation (H/R). In addition, HDAC6 global‐knockout (HDAC6‐KO) mice, adeno‐associated virus‐mediated liver‐specific HDAC6 overexpressing (HDAC6‐LTG) mice, and their corresponding controls were used to construct hepatic IRI models. Hepatic histology, inflammatory responses, and apoptosis were detected to assess liver injury. The molecular mechanisms of HDAC6 in hepatic IRI were explored in vivo and in vitro. Moreover, the HDAC6‐selective inhibitor tubastatin A was used to detect the therapeutic effect of HDAC6 on liver IRI. Together, our results showed that HDAC6 expression was significantly upregulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Compared with control mice, HDAC6 deficiency mitigated liver IRI by inhibiting inflammatory responses and apoptosis, whereas HDAC6‐LTG mice displayed the opposite phenotype. Further molecular experiments show that HDAC6 bound to and deacetylated AKT and HDAC6 deficiency improved liver IRI by activating PI3K/AKT/mTOR signaling. In conclusion, HDAC6 is a key mediator of hepatic IRI that functions to promote inflammation and apoptosis via PI3K/AKT/mTOR signaling. Targeting hepatic HDAC6 inhibition may be a promising approach to attenuate liver IRI.

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“…The aberrant activation of the KIF2C -regulated PI3K/AKT/MAPK3 signaling pathway may increase cellular resistance to cisplatin. In HCC cells, the high expression of KIF2C may increase the activity of PI3K by interacting with PI3K, an important signaling protein that initiates the AKT signaling pathway [34,35]. The AKT signaling pathway plays a key role in cell survival, proliferation, and drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Silencing of KIF2C enhances the sensitivity of hepatocellular carcinoma cells to cisplatin through regulating the PI3K/AKT/MAPK signaling pathway

Wei,

Lu,

et al. 2023

Anti-Cancer Drugs

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In the treatment of unresectable advanced hepatocellular carcinoma (HCC), cisplatin is administered transhepatic arterially for local treatment, but the clinical application of cisplatin drugs is frequently hindered by the emergence of drug resistance. Kinesin family member 2C(KIF2C) has been shown as oncogene in a variety of tumors. Nevertheless, its effect on cisplatin sensitivity has yet to be ascertained. Herein, we aim to investigate the impact of the KIF2C gene on cisplatin sensitivity within HCC and the plausible underlying molecular mechanism. We examined the expression level of the KIF2C gene in HCC cells by real-time quantitative reverse transcription PCR and Western blot analysis, and analyzed bioinformatically by The Gene Expression Omnibus database and The Cancer Genome Atlas database. The KIF2C gene was silenced using the small interfering RNA technology, and its effect on cisplatin drug sensitivity in HCC cells was evaluated by flow cytometry, cell proliferation, cell migration, and invasion assays. Our results indicated that KIF2C was highly expressed in HCC cells. KIF2C silencing inhibits HCC cell proliferation, migration and invasion, promotes apoptosis, and keeps the cell cycle in G2 phase. In addition, KIF2C silencing enhanced the sensitivity of HCC cells to cisplatin. KIF2C silencing down-regulates the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and mitogen-activated protein kinase 3 (MAPK3) proteins. In conclusion, KIF2C silencing amplifies the sensitivity of HCC cells to cisplatin by regulating the PI3K/AKT/MAPK signaling pathway. Consequently, targeting KIF2C shows great application potential as a strategy for enhancing the effectiveness of HCC treatment.

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Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and Challenges

Cited by 70 publications

References 374 publications

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Silencing of KIF2C enhances the sensitivity of hepatocellular carcinoma cells to cisplatin through regulating the PI3K/AKT/MAPK signaling pathway

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