Silencing &lt;italic&gt;KIF14&lt;/italic&gt; reverses acquired resistance to sorafenib in hepatocellular carcinoma

Zhu, Qiankun; Ren, Hai-Yang; Li, Xiaodong; Qian, Bo; Fan, Shengjie; Hu, Fengli; Xu, Lishan; Zhai, Bo

doi:10.18632/aging.104028

Cited by 8 publications

(9 citation statements)

References 71 publications

(87 reference statements)

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“…S5E, F ). An involvement of AKT in the induction of Ets-1 in sorafenib resistance has also been shown, which involves kinesin family member 14 (KIF14) [ 81 ]. In addition, HGF/c-met axis has been linked with sorafenib resistance [ 82 , 83 ], and since this axis is also known to induce Ets-1 in HCCs this could be a potential mechanism by which Ets-1 is induced in sora-resistance.…”

Section: Discussionmentioning

confidence: 99%

Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma

Vishnoi

Viswakarma

et al. 2022

Cell Death Dis

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The incidence and mortality of hepatocellular carcinoma (HCC) are on a rise in the Western countries including US, attributed mostly to late detection. Sorafenib has been the first-line FDA-approved drug for advanced unresectable HCC for almost a decade, but with limited efficacy due to the development of resistance. More recently, several other multi-kinase inhibitors (lenvatinib, cabozantinib, regorafenib), human monoclonal antibody (ramucirumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab) have been approved as systemic therapies. Despite this, the median survival of patients is not significantly increased. Understanding of the molecular mechanism(s) that govern HCC resistance is critically needed to increase efficacy of current drugs and to develop more efficacious ones in the future. Our studies with sorafenib-resistant (soraR) HCC cells using transcription factor RT2 Profiler PCR Arrays revealed an increase in E26 transformation–specific-1 (Ets-1) transcription factor in all soraR cells. HCC TMA studies showed an increase in Ets-1 expression in advanced HCC compared to the normal livers. Overexpression or knocking down Ets-1 modulated sorafenib resistance-related epithelial–mesenchymal transition (EMT), migration, and cell survival. In addition, the soraR cells showed a significant reduction of mitochondrial damage and mitochondrial reactive oxygen species (mROS) generation, which were antagonized by knocking down Ets-1 expression. More in-depth analysis identified GPX-2 as a downstream mediator of Ets-1-induced sorafenib resistance, which was down-regulated by Ets-1 knockdown while other antioxidant pathway genes were not affected. Interestingly, knocking down GPX2 expression significantly increased sorafenib sensitivity in the soraR cells. Our studies indicate the activation of a novel Ets-1–GPX2 signaling axis in soraR cells, targeting which might successfully antagonize resistance and increase efficacy.

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Section: Discussionmentioning

confidence: 99%

Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma

Vishnoi

Viswakarma

et al. 2022

Cell Death Dis

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“…For example, kinesin family member 14 (KIF14), a microtubule-dependent cytoskeletal motor protein, is involved in cytokinesis [ 45 ]. KIF14 overexpression is linked to several cancers, and KIF14 causes resistance to sorafenib and chemotherapy through the AKT signaling pathway in cancers [ 46 , 47 ]. KIF14 has been shown to be oncogenic in several studies and has been reported as a prognostic biomarker for several cancers, but its relative importance as a driver gene in lung cancer pathogenesis is yet to be clarified [ 46 – 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…KIF14 overexpression is linked to several cancers, and KIF14 causes resistance to sorafenib and chemotherapy through the AKT signaling pathway in cancers [ 46 , 47 ]. KIF14 has been shown to be oncogenic in several studies and has been reported as a prognostic biomarker for several cancers, but its relative importance as a driver gene in lung cancer pathogenesis is yet to be clarified [ 46 – 49 ]. Corson et al discovered that KIF14 expression was an independent prognostic factor for disease-free survival in NSCLC and knockdown of KIF14 in vitro reduced tumorigenicity [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a GPX4-Related Immune Prognostic Signature for Lung Adenocarcinoma

Feng

Chen

et al. 2022

Journal of Oncology

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Lung adenocarcinoma (LUAD) is a commonly occurring histological subtype of lung cancer. Glutathione peroxidase 4 (GPX4) is an important regulatory factor of ferroptosis and is involved in the development of many cancers, but its prognostic significance has not been systematically described in LUAD. In this study, we focused on developing a robust GPX4-related prognostic signature (GPS) for LUAD. Data for the training cohort was extracted from The Cancer Genome Atlas, and that for the validation cohort was sourced from the GSE72094 dataset including 863 LUAD patients. GPX4-related genes were screened out by weighted gene coexpression network analysis and Spearman’s correlation analysis. Then, Cox regression and least absolute shrinkage and selection operator regression analyses were employed to construct a GPS. The ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and GSEA were utilized to evaluate the relationship between GPS and the tumor microenvironment (TME). We constructed and validated a GPS premised on four GPX4-related genes (KIF14, LATS2, PRKCE, and TM6SF1), which could classify LUAD patients into low- and high-score cohorts. The high-risk cohort presented noticeably poorer overall survival (OS) as opposed to the low-risk cohort, meaning that the GPS may be utilized as an independent predictor of the OS of LUAD. The GPS was also adversely correlated with multiple tumor-infiltrating immune cells and immune-related processes and pathways in TME. Furthermore, greater sensitivity to erlotinib and lapatinib were identified in the low-risk cohort based on the GDSC database. Our findings suggest that the GPS can effectively forecast the prognosis of LUAD patients and may possibly regulate the TME of LUAD.

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“…Sorafenib is the rst-line targeted agent that prolongs the median survival time of patients with advanced HCC by nearly three months; unfortunately, most patients develop resistance to this drug within six months 21 . The mechanisms by which HCC develops resistance to sorafenib are largely unknown, although some molecular events such as Hedgehog signaling, Jak-STAT pathway, oncogene KIF14, and IGF/FGF signaling have been suggested to be related to sorafenib resistance in HCC 10,11,22,23 . Here, we induced acquired sorafenib-resistant organoids from four HCC patients following 3-5 months of culture.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity, Inherent and Acquired Drug Resistance in Patient-Derived Organoids Models of Primary Liver Cancer

Cao¹,

Xian²,

Zhao³

et al. 2022

Preprint

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To screen for sensitive drugs for recurrent primary liver cancer (PLC) and elucidate the mechanisms underlying inherent and acquired drug resistance, we established a platform of organoids, organoids-derived xenograft (ODX) mouse models, and patient-derived xenograft (PDX) mouse models of primary liver cancer (PLC). Fifty-two organoids were established from 153 PLC patients. Establishing organoids of hepatocellular carcinoma (HCC) displayed a trend toward a higher success rate than establishing PDX (29.0% vs. 23.7%) and took a shorter duration (13.0 ± 4.7 vs. 25.1 ± 5.4 days, P=2.28×10−13) than establishing PDX models. Larger tumor, vascular invasion, and advanced stage were significantly associated with successful establishment of organoids and PDX in HCC. Organoids and ODX recapitulated PLC histopathological features but enriched more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive in ODX model, indicating innate immunity plays a role. Acquired sorafenib-resistant HCC organoids were generated via 3–5 months of induction. RNA-sequencing indicated that stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated, in acquired sorafenib-resistant organoids. Targeting mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were often associated with unfavorable prognosis. Conclusively, HCC organoids perform better than PDX for drug selection. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating the stemness, retrodifferentiation, and EMT. Phosphorylated S6 kinase might be predictive for drug resistance in HCC.

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Silencing <italic>KIF14</italic> reverses acquired resistance to sorafenib in hepatocellular carcinoma

Cited by 8 publications

References 71 publications

Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma

Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma

Identification and Validation of a GPX4-Related Immune Prognostic Signature for Lung Adenocarcinoma

Heterogeneity, Inherent and Acquired Drug Resistance in Patient-Derived Organoids Models of Primary Liver Cancer

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