KRAS Hijacks the miRNA Regulatory Pathway in Cancer

Bortoletto, Angelina S.; Parchem, Ronald J.

doi:10.1158/0008-5472.can-23-0296

Cited by 15 publications

(11 citation statements)

References 145 publications

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“…Thus we are led to speculate that cells able to adapt to chronic Ras-mediated signalling may become cancerous, in part, by sometimes activating stemness pathways that also confer reoviral susceptibility. We are therefore intrigued by the recent observation that Ras expression can modulate miRNA signalling, opening new possibilities for altering multiple downstream pathways, including cellular stemness [ 95 ]. In addition, an investigation of primitive gut stem cells or induced stem cells in the digestive tract that are possible natural hosts for viral infection in humans and other animals could yield further insights into mechanisms of viral cytolysis [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of Reoviral Cytolysis (II): Cellular Stemness

Bourhill

Rohani

Kumar

et al. 2023

Viruses

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Oncolytic viruses (OVs) are an emerging cancer therapeutic that are intended to act by selectively targeting and lysing cancerous cells and by stimulating anti-tumour immune responses, while leaving normal cells mainly unaffected. Reovirus is a well-studied OV that is undergoing advanced clinical trials and has received FDA approval in selected circumstances. However, the mechanisms governing reoviral selectivity are not well characterised despite many years of effort, including those in our accompanying paper where we characterize pathways that do not consistently modulate reoviral cytolysis. We have earlier shown that reovirus is capable of infecting and lysing both certain types of cancer cells and also cancer stem cells, and here we demonstrate its ability to also infect and kill healthy pluripotent stem cells (PSCs). This led us to hypothesize that pathways responsible for stemness may constitute a novel route for the modulation of reoviral tropism. We find that reovirus is capable of killing both murine and human embryonic and induced pluripotent stem cells. Differentiation of PSCs alters the cells’ reoviral-permissive state to a resistant one. In a breast cancer cell line that was resistant to reoviral oncolysis, induction of pluripotency programming rendered the cells permissive to cytolysis. Bioinformatic analysis indicates that expression of the Yamanaka pluripotency factors may be associated with regulating reoviral selectivity. Mechanistic insights from these studies will be useful for the advancement of reoviral oncolytic therapy.

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Section: Discussionmentioning

confidence: 99%

Modulation of Reoviral Cytolysis (II): Cellular Stemness

Bourhill

Rohani

Kumar

et al. 2023

Viruses

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“…As discussed in the literature [74], oncogenic mutations in factors involved in miRNA biosynthesis, processing, and export machinery are associated with many cancers. The majority of these oncogenic mutations in the microprocessing complex and export machinery result in a decrease in miRNA biosynthesis, leading to global dysregulation of miRNAs and the mRNA transcripts they regulate.…”

Section: Oncogenic Mutations In Key Factors Involved In the Mirna Bio...mentioning

confidence: 99%

“…For example, it has been shown that genetic deletion or amplification, epigenetic methylation of miRNA genomic loci, and alterations affecting the transcription factor-mediated regulation of primary miRNA (pri-miRNA) as well as components involved in the miRNA biogenesis pathway frequently alter miRNA expression and function in many cancers. In addition, recent data indicate that other factors including oncogenic drivers such as mutations in the KRAS gene can also affect global miRNA biogenesis and effector function, leading to global miRNA dysregulation [74]. Because of this, miRNAs and their dysregulation have gained attention both from academia and industry as a research discipline both for understanding disease biology [59,[75][76][77] and to develop them as potential diagnostic, prognostic, and predictive biomarkers as well as drug targets or as therapeutics [47,48,51,59,67,78].…”

Section: Introductionmentioning

confidence: 99%

Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer—Advances and Challenges

Seyhan

2023

IJMS

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There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers.

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“…These mutations can lead to global miRNA deregulation which may promote hallmarks of cancer. Interestingly, recent evidence proposes that oncogenic KRAS mutations modulate the activity of members of the miRNA regulatory pathway and consequently enhance tumorigenesis [ 79 ]. miRNAs are now being developed as diagnostic and as predictive or prognostic tools.…”

Section: Conclusion and Future Prospectivementioning

confidence: 99%

Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma

Vahabi,

Dehni,

Antomás

et al. 2023

Cancer Metastasis Rev

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor prognosis due to early metastasis, low diagnostic rates at early stages, and resistance to current therapeutic regimens. Despite numerous studies and clinical trials, the mortality rate for PDAC has shown limited improvement. Therefore, there is a pressing need to attain. a more comprehensive molecular characterization to identify biomarkers enabling early detection and evaluation of treatment response. MicroRNA (miRNAs) are critical regulators of gene expression on the post-transcriptional level, and seem particularly interesting as biomarkers due to their relative stability, and the ability to detect them in fixed tissue specimens and biofluids. Deregulation of miRNAs is common and affects several hallmarks of cancer and contribute to the oncogenesis and metastasis of PDAC. Unique combinations of upregulated oncogenic miRNAs (oncomiRs) and downregulated tumor suppressor miRNAs (TsmiRs), promote metastasis, characterize the tumor and interfere with chemosensitivity of PDAC cells. Here, we review several oncomiRs and TsmiRs involved in chemoresistance to gemcitabine and FOLFIRINOX in PDAC and highlighted successful/effective miRNA-based therapy approaches in vivo. Integrating miRNAs in PDAC treatment represents a promising therapeutic avenue that can be used as guidance for personalized medicine for PDAC patients.

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KRAS Hijacks the miRNA Regulatory Pathway in Cancer

Cited by 15 publications

References 145 publications

Modulation of Reoviral Cytolysis (II): Cellular Stemness

Modulation of Reoviral Cytolysis (II): Cellular Stemness

Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer—Advances and Challenges

Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma

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