Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic “dual-hit” option

Dietrich, Péter; Freese, K; Mahli, A; Thasler, Wolfgang E.; Hellerbrand, Claus; Bosserhoff, Anja‐Katrin

doi:10.18632/oncotarget.23188

Cited by 29 publications

(33 citation statements)

References 60 publications

(89 reference statements)

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“…Many oncogenes, growth factors, and tumor suppressor genes have been identified in processes of hepatocarcinogenesis 22 – 25 , however, the molecular carcinogenic mechanisms and the pathogenic biology of HCC remains unclear 22 , 26 – 28 . A growing amount of experimental evidence has been supporting a significant role for miRNAs in tumorigenesis of HCC 27 , 29 , 30 .…”

Section: Disscussionmentioning

confidence: 99%

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN

Lin

Huang

Liu

et al. 2018

Sci Rep

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Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.

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Section: Disscussionmentioning

confidence: 99%

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN

Lin

Huang

Liu

et al. 2018

Sci Rep

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“…In most recent studies, our group showed that the wild-type RAS isoform Kirsten rat sarcoma (KRAS) is a promising candidate diagnostic and therapeutic target majorly contributing to acquired resistance to RAF inhibitors in HCC and other types of cancer [9], [10], [11]. Moreover, we found that the HRas proto-oncogene (HRAS) isoform is upregulated in HCC and affects patient outcome [12].…”

Section: Introductionmentioning

confidence: 99%

Neuroblastoma RAS Viral Oncogene Homolog (NRAS) Is a Novel Prognostic Marker and Contributes to Sorafenib Resistance in Hepatocellular Carcinoma

et al. 2019

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Inhibition of the RAS-RAF-ERK-pathway using sorafenib as a first-line and regorafenib as a second-line treatment approach is the only effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). Recent studies suggest that wild-type KRAS and HRAS isoforms could majorly contribute to HCC progression and sorafenib resistance. In contrast, the role of neuroblastoma RAS viral oncogene homolog (NRAS) in HCC remained elusive. In this study, wild-type NRAS was found to be overexpressed in HCC cell lines, preclinical HCC models, and human HCC tissues. Moreover, NRAS overexpression correlated with poor survival and proliferation in vivo. However, si-RNA-pool–mediated NRAS knockdown showed only slight effects on HCC proliferation, clonogenicity, and AKT activity. We determined that KRAS upregulation served as a functional compensatory mechanism in the absence of NRAS, which was overcome by combined inhibition of NRAS and KRAS in HCC cells. Furthermore, NRAS expression was elevated in sorafenib-resistant compared to nonresistant HCC cells, and NRAS knockdown enhanced sorafenib efficacy in resistant cells. In summary, NRAS appears to be a prognostic marker in HCC and contributes to sorafenib resistance. Regarding potential therapeutic strategies, NRAS inhibition in HCC should be combined with KRAS inhibition to prevent KRAS-mediated rescue effects.

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“…Some studies have demonstrated that PLK1 was closely associated with RAS/MEK/ERK pathways, including regulation of MEK1/2 and proliferation in airway smooth muscle cells, 36 induction of epithelial-to-mesenchymal transition and promotion of epithelial cell motility by activating CRAF/ERK signaling, 37 and activation by RAS-RAF signaling as a therapeutic target in HCC. 38 As a result, we explore the relationship between PLK1 and RAS/MEK/ERK in GC. The Western blotting and in vivo assays demonstrated the inhibition of PLK1 activity with BI6727 significantly blocked MEK/ERK phosphorylation and activation, resulting in an obvious reduction in tumor volume and weight.…”

Section: Discussionmentioning

confidence: 99%

PLK1 as a potential prognostic marker of gastric cancer through MEK-ERK pathway on PDTX models

Dang¹,

Fan²,

Cui³

et al. 2018

OTT

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BackgroundPLK1 has been identified as having a great effect on cell division and maintaining genomic stability in mitosis, spindle assembly, and DNA damage response by current studies.Materials and methodsWe assessed PLK1 expression in cervical cancer tissues and cells. We have also evaluated the effects of PLK1 on gastric cancer cell proliferation, migration, and apoptosis both in vitro and in vivo.ResultsOur results show that PLK1 is overexpressed in gastric cancer tissues and cells. Inhibition of PLK1 contributes cell cycle G2-phase arrest and inhibits the proliferation, migration, and apoptosis of gastric cancer (GC) cells, whereas its overexpression promotes proliferation, migration, and apoptosis in these cells. Moreover, PLK1 inhibition reduces expression of pMEK and pERK. More importantly, in vivo by analyzing tumorigenesis in patient-derived tumor xenograft (PDTX) models, the inhibition of PLK1 activity by BI6727 significantly decreased the volume and weight of the tumors compared with control group (P<0.01).ConclusionOur results found that PLK1 has a significant impact on the survival of GC cells; it may become a prognostic judge, a potential therapeutic target, and a preventative biomarker of GC.

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Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic “dual-hit” option

Cited by 29 publications

References 60 publications

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN

Neuroblastoma RAS Viral Oncogene Homolog (NRAS) Is a Novel Prognostic Marker and Contributes to Sorafenib Resistance in Hepatocellular Carcinoma

PLK1 as a potential prognostic marker of gastric cancer through MEK-ERK pathway on PDTX models

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