Oral mucositis: the hidden side of cancer therapy Pulito, Claudio; Cristaudo, Antonio; Porta, Caterina La ...
Journal of experimental & clinical cancer research,
10/2020, Letnik:
39, Številka:
1
Journal Article
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Inflammation response of epithelial mucosa to chemo- radiotherapy cytotoxic effects leads to mucositis, a painful side effect of antineoplastic treatments. About 40% of the patients treated with ...chemotherapy develop mucositis; this percentage rises to about 90% for head and neck cancer patients (HNC) treated with both chemo- and radiotherapy. 19% of the latter will be hospitalized and will experience a delay in antineoplastic treatment for high-grade mucositis management, resulting in a reduction of the quality of life, a worse prognosis and an increase in patient management costs. Currently, several interventions and prevention guidelines are available, but their effectiveness is uncertain. This review comprehensively describes mucositis, debating the impact of standard chemo-radiotherapy and targeted therapy on mucositis development and pointing out the limits and the benefits of current mucositis treatment strategies and assessment guidelines. Moreover, the review critically examines the feasibility of the existing biomarkers to predict patient risk of developing oral mucositis and their role in early diagnosis. Despite the expression levels of some proteins involved in the inflammation response, such as TNF-alpha or IL-1beta, partially correlate with mucositis process, their presence does not exclude others mucositis-independent inflammation events. This strongly suggests the need to discover biomarkers that specifically feature mucositis process development. Non-coding RNAs might hold this potential. Keywords: Oral mucositis, HNC, Biomarker, Cytokine, Non-coding RNA, Quality of life
Lung cancer is the leading cause of cancer-related deaths, worldwide. Non–small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. YAP and TAZ have been implicated in lung cancer by ...acting as transcriptional co-activators of oncogenes or as transcriptional co-repressors of tumor suppressor genes. Previously we reported that YAP and TAZ regulate microRNAs expression in NSCLC. Among the set of regulated miRNAs, the oncogenic miR-25, 93, and 106b, clustering within the MCM7 gene were selected for further studies. We firstly identified Transforming Growth Factor-β (TGF-β) Receptor 2 (TGFBR2), a member of the TGF-β signaling, as a target of the miRNA cluster, which exhibited prognostic value because of its tumor suppressor activity. We found that YAP/TAZ-mediated repression of TGFBR2 occurs both: post-transcriptionally through the miR-106b-25 cluster and transcriptionally by engaging the EZH2 epigenetic repressor that we reported here as a novel target gene of YAP/TAZ. Furthermore, we document that YAP/TAZ and EZH2 cooperate in lung tumorigenesis by transcriptionally repressing a specific subset of tumor suppressor genes, including TGFBR2. Our findings point to YAP/TAZ and EZH2 as potential therapeutic targets for NSCLC treatment.
•YAP/TAZ post-transcriptionally inhibit TGFBR2 through the oncogenic miR 25/93/106b.•YAP and TAZ transcriptionally regulate the epigenetic repressor EZH2.•YAP/TAZ and EZH2 transcriptionally co-repress oncosuppressor genes, including TGFBR2.•Inhibition of YAP/TAZ and EZH2 re-activates oncosuppressor genes in NSCLC.•Combined inhibition of YAP/TAZ and EZH2 is a potential therapeutic strategy in NSCLC.
The role of circular RNAs in oncogenesis has begun to be widely studied in recent years, due to the significant impact that these molecules have in disease pathogenesis, as well as their potential ...for the future of innovative therapies. Moreover, due to their characteristically circular shape, circular RNAs are very resistant molecules to RNA degradation whose levels are easily assessed in body fluids. Accordingly, they represent an opportunity for the discovery of new diagnostic and prognostic markers in a wide range of diseases. Among circular RNAs, circPVT1 is a rather peculiar one that originates from the circularization of the exon 2 of the PVT1 gene that encodes a pro-tumorigenic long non-coding RNA named lncPVT1. There are a few examples of circular RNAs that derive from a locus producing another non-coding RNA. Despite their apparent transcriptional independence, which occurs using two different promoters, a possible synergistic effect in tumorigenesis cannot be excluded considering that both have been reported to correlate with the oncogenic phenotype. This complex mechanism of regulation appears to also be controlled by c-MYC. Indeed, the PVT1 locus is located only 53 Kb downstream c-MYC gene, a well-known oncogene that regulates the expression levels of about 15% of all genes. Here, we review circPVT1 origin and biogenesis highlighting the most important mechanisms through which it plays a fundamental role in oncogenesis, such as the well-known sponge activity on microRNAs, as well as its paradigmatic interactome link with lncPVT1 and c-MYC expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diabetic patients treated with metformin have a reduced incidence of cancer and cancer-related mortality. Here we show that metformin affects engraftment and growth of breast cancer tumours in mice. ...This correlates with the induction of metabolic changes compatible with clear anticancer effects. We demonstrate that microRNA modulation underlies the anticancer metabolic actions of metformin. In fact, metformin induces DICER expression and its effects are severely impaired in DICER knocked down cells. Conversely, ectopic expression of DICER recapitulates the effects of metformin in vivo and in vitro. The microRNAs upregulated by metformin belong mainly to energy metabolism pathways. Among the messenger RNAs downregulated by metformin, we found c-MYC, IRS-2 and HIF1alpha. Downregulation of c-MYC requires AMP-activated protein kinase-signalling and mir33a upregulation by metformin. Ectopic expression of c-MYC attenuates the anticancer metabolic effects of metformin. We suggest that DICER modulation, mir33a upregulation and c-MYC targeting have an important role in the anticancer metabolic effects of metformin.
Sperm-associated antigen 5 (SPAG5) is an important driver of the cell mitotic spindle required for chromosome segregation and progression into anaphase. SPAG5 has been identified as an important ...proliferation marker and chemotherapy-sensitivity predictor, especially in estrogen receptor-negative breast cancer subtypes. Here, we report that SPAG5 is a direct target of miR-10b-3p, and its aberrantly high expression associates with poor disease-free survival in two large cohorts of breast cancer patients. SPAG5 depletion strongly impaired cancer cell cycle progression, proliferation, and migration. Interestingly, high expression of SPAG5 pairs with a YAP/TAZ-activated signature in breast cancer patients. Reassuringly, the depletion of YAP, TAZ, and TEAD strongly reduced SPAG5 expression and diminished its oncogenic effects. YAP, TAZ coactivators, and TEAD transcription factors are key components of the Hippo signaling pathway involved in tumor initiation, progression, and metastasis. Furthermore, we report that SPAG5 is a direct transcriptional target of TEAD/YAP/TAZ, and pharmacological targeting of YAP and TAZ severely reduces SPAG5 expression. Collectively, our data uncover an oncogenic feedback loop, comprising miR-10b-3p, SPAG5, and YAP/TAZ/TEAD, which fuels the aberrant proliferation of breast cancer.
Breast cancer is one of the most frequent causes of cancer death among women worldwide. In particular, triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype ...because it is characterized by the absence of molecular targets, thus making it an orphan type of malignancy. The discovery of new molecular druggable targets is mandatory to improve treatment success. In that context, non-coding RNAs represent an opportunity for modulation of cancer. They are RNA molecules with apparently no protein coding potential, which have been already demonstrated to play pivotal roles within cells, being involved in different processes, such as proliferation, cell cycle regulation, apoptosis, migration, and diseases, including cancer. Accordingly, they could be used as targets for future TNBC personalized therapy. Moreover, the peculiar characteristics of non-coding RNAs make them reliable biomarkers to monitor cancer treatment, thus, to monitor recurrence or chemoresistance, which are the most challenging aspects in TNBC. In the present review, we focused on the oncogenic or oncosuppressor role of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) mostly involved in TNBC, highlighting their mode of action and depicting their potential role as a biomarker and/or as targets of new non-coding RNA-based therapeutics.
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide. They are typically characterized by a high incidence of local recurrence, which is the most common cause of death ...in HNSCC patients. TP53 is the most frequently mutated gene in HNSCC and patients carrying TP53 mutations are associated with a higher probability to develop local recurrence. MiRNAs, which are among the mediators of the oncogenic activity of mt-p53 protein, emerge as an appealing tool for screening, diagnosis and prognosis of cancer. We previously identified a signature of 12 miRNAs whose aberrant expression associated with TP53 mutations and was prognostic for HNSCC. Among them miR-96-5p emerges as an oncogenic miRNAs with prognostic significance in HNSCC.
To evaluate the oncogenic role of miR-96-5p in a tumoral context, we performed colony formation, cell migration and cell viability assays in two HNSCC cell lines transfected for miR-96-5p mimic or inhibitor and treated with or without radio/chemo-therapy. In addition, to identify genes positively and negatively correlated to miR-96-5p expression in HNSCC, we analyzed the correlation between gene expression and miR-96-5p level in the subset of TCGA HNSCC tumors carrying missense TP53 mutations by Spearman and Pearson correlation. To finally identify targets of miR-96-5p, we used in silico analysis and the luciferase reporter assay to confirm PTEN as direct target.
Our data showed that overexpression of miR-96-5p led to increased cell migration and radio-resistance, chemotherapy resistance in HNSCC cells. In agreement with these results, among the most statistically significant pathways in which miR-96-5p is involved, are focal Adhesion, extracellular matrix organization and PI3K-Akt-mTOR-signaling pathway. As a direct target of miR-96-5p, we identified PTEN, the main negative regulator of PI3K-Akt signalling pathway activation.
These results highlight a new mechanism of chemo/radio-resistance insurgence in HNSCC cells and support the possibility that miR-96-5p expression could be used as a novel promising biomarker to predict radiotherapy response and local recurrence development in HNSCC patients. In addition, the identification of pathways in which miR-96-5p is involved could contribute to develop new therapeutic strategies to overcome radio-resistance.
Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may ...increase the therapeutic benefit and allow studying new approaches for resistant patients.
We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines.
We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings.
Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and ...micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to the metabolic plasticity which characterizes cancer cell subpopulations-capable of adaptive switching under stress conditions, between aerobic glycolysis and oxidative phosphorylation-in both a convergent and divergent modality. The mitochondria appear at center-stage in this adaptive process and thus, targeting mitochondria in cancer may prove of therapeutic value. Metformin is the oldest and most used anti-diabetic medication and its relationship with cancer has witnessed rises and falls in the last 30 years. We believe it is useful to revisit the main mechanisms of action of metformin in light of the emerging views on tumor heterogeneity. We first analyze the most consolidated view of its mitochondrial mechanism of action and then we frame the latter in the context of tumor adaptive strategies, cancer stem cell selection, metabolic zonation of tumors and the tumor microenvironment. This may provide a more critical point of view and, to some extent, may help to shed light on some of the controversial evidence for metformin's anticancer action.
Understanding the mechanisms of breast cancer cell communication underlying cell spreading and metastasis formation is fundamental for developing new therapies. ID4 is a proto-oncogene overexpressed ...in the basal-like subtype of triple-negative breast cancer (TNBC), where it promotes angiogenesis, cancer stem cells, and BRACA1 misfunction. Here, we show that ID4 expression in BC cells correlates with the activation of motility pathways and promotes the production of VEGFA, which stimulates the interaction of VEGFR2 and integrin β3 in a paracrine fashion. This interaction induces the downstream focal adhesion pathway favoring migration, invasion, and stress fiber formation. Furthermore, ID4/ VEGFA/ VEGFR2/ integrin β3 signaling stimulates the nuclear translocation and activation of the Hippo pathway member's YAP and TAZ, two critical executors for cancer initiation and progression. Our study provides new insights into the oncogenic roles of ID4 in tumor cell migration and YAP/TAZ pathway activation, suggesting VEGFA/ VEGFR2/ integrin β3 axis as a potential target for BC treatment.
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