Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells

Zichittella, Chiara; Barreca, Maria Magdalena; Cordaro, Aurora; Corrado, Chiara; Alessandro, Riccardo; Conigliaro, Alice

doi:10.1186/s12885-022-09666-2

Cited by 13 publications

(10 citation statements)

References 54 publications

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“…A prevalent example is miR-675-5p, an miRNA with an established oncogenic role in CRC [ 56 ]. In particular, several studies have investigated the functional role of miR-675-5p in CRC, which is suggested to support hypoxia-induced EMT in colon cancer cells and promote CRC cell growth and drug resistance [ 24 , 26 , 27 ]. However, the clinical significance of miR-675-5p as a molecular marker has not been investigated yet.…”

Section: Discussionmentioning

confidence: 99%

“…Costa et al demonstrated that miR-675-5p is overexpressed in metastatic colon cancer cells, promoting EMT by controlling hypoxia-inducible factor 1 subunit alpha (HIF1a) [ 26 ]. In addition, the hypoxic tumor microenvironment in CRC induces the expression levels of miR-675-5p, thereby enhancing drug resistance [ 27 ]. It may seem counter-intuitive that miR-675-5p levels are downregulated in the majority of colorectal adenocarcinoma tissues compared to those in adjacent normal colorectal tissues, whereas miR-675-5p overexpression is being suggested as a predictor of adverse prognosis in this malignancy.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, APC , GSK3 , and TCF4 are among the WNT/β-catenin pathway targets of miR-675-5p, according to reports [ 24 , 25 , 26 ]. Furthermore, higher levels of miR-675-5p have been associated with increased sensitivity to chemotherapy drugs, such as 5-fluorouracil (5-FU) [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer

Christodoulou

Sotiropoulou

Vassiliu

et al. 2023

IJMS

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Colorectal cancer (CRC) is the main cause of cancer-related deaths globally, highlighting the importance of accurate biomarkers for early detection and accurate prognosis. MicroRNAs (miRNAs) have emerged as effective cancer biomarkers. The aim of this study was to investigate the prognostic potential of miR-675-5p as a molecular prognostic biomarker in CRC. For this reason, a quantitative PCR assay was developed and applied to determine miR-675-5p expression in cDNAs from 218 primary CRC and 90 paired normal colorectal tissue samples. To assess the significance of miR-675-5p expression and its association with patient outcome, extensive biostatistical analysis was performed. miR-675-5p expression was found to be significantly downregulated in CRC tissue samples compared to that in adjacent normal colorectal tissues. Moreover, high miR-675-5p expression was associated with shorter disease-free (DFS) and overall survival (OS) in CRC patients, while it maintained its unfavorable prognostic value independently of other established prognostic factors. Furthermore, TNM stage stratification demonstrated that higher miR-675-5p levels were associated with shorter DFS and OS intervals, particularly in patients with CRC of TNM stage II or III. In conclusion, our findings suggest that miR-675-5p overexpression constitutes a promising molecular biomarker of unfavorable prognosis in CRC, independent of other established prognostic factors, including TNM staging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer

Christodoulou

Sotiropoulou

Vassiliu

et al. 2023

IJMS

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“…In addition, HIF has been reported to promote docetaxel resistance in triple-negative breast cancer cells by suppressing miR-494 expression to enhance Survivin expression [47]. Furthermore, HIF is known to cause oxaliplatin resistance in colorectal cancer by inducing miR-338-5p expression under hypoxia to promote IL-6 signaling, which, in turn, suppresses apoptosis via the STAT3/BCL2 pathway [48][49][50].…”

Section: Hif-mediated Mechanisms Behind Chemotherapy Resistancementioning

confidence: 99%

Hypoxia-Inducible Factor-Dependent and Independent Mechanisms Underlying Chemoresistance of Hypoxic Cancer Cells

Lee,

Koseki,

Haitani

et al. 2024

Cancers

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In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified.

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“…We have recently demonstrated that lncH19-derived miR-675-5p enforces hypoxia-induced chemoresistance to 5-FU by targeting pro-caspase-3 and inhibiting the pro-apoptotic effects of 5-FU (Zichittella et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA H19 enhances the pro-apoptotic activity of ITF2357 (a histone deacetylase inhibitor) in colorectal cancer cells

Zichittella,

Loria,

Celesia

et al. 2023

Front. Pharmacol.

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Introduction: Long non-coding RNA H19 (lncH19) is highly expressed in colorectal cancer (CRC) and plays critical roles in tumor development, proliferation, metastasis, and drug resistance. Indeed, the expression of lncH19 usually affects the outcomes of chemo-, endocrine, and targeted therapies. ITF2357 (givinostat) is a histone deacetylase inhibitor (HDACi) that revealed a significant anti-tumor action by inducing apoptosis in different tumor models, including leukemia, melanoma, and glioblastoma. However, no data are present in the literature regarding the use of this compound for CRC treatment. Here, we investigate the role of lncH19 in ITF2357-induced apoptosis in CRC cells.Methods: The HCT-116 CRC cell line was stably silenced for H19 to investigate the role of this lncRNA in ITF2357-induced cell death. Cell viability assays and flow cytometric analyses were performed to assess the anti-proliferative and pro-apoptotic effects of ITF2357 in CRC cell lines that are silenced or not for lncH19. RT-PCR and Western blot were used to study the effects of ITF2357 on autophagy and apoptosis markers. Finally, bioinformatics analyses were used to identify miRNAs targeting pro-apoptotic factors that can be sponged by lncH19.Results: ITF2357 increased the expression levels of H19 and reduced HCT-116 cell viability, inducing apoptosis, as demonstrated by the increase in annexin-V positivity, caspase 3 cleavage, and poly (ADP-ribose) polymerase (PARP-1) degradation. Interestingly, the apoptotic effect of ITF2357 was much less evident in lncH19-silenced cells. We showed that lncH19 plays a functional role in the pro-apoptotic activity of the drug by stabilizing TP53 and its transcriptional targets, NOXA and PUMA. ITF2357 also induced autophagy in CRC cells, which was interpreted as a pro-survival response not correlated with lncH19 expression. Furthermore, ITF2357 induced apoptosis in 5-fluorouracil-resistant HCT-116 cells that express high levels of lncH19.Conclusion: This study shows that lncH19 expression contributes to ITF2357-induced apoptosis by stabilizing TP53. Overall, we suggest that lncH19 expression may be exploited to favor HDACi-induced cell death and overcome 5-fluorouracil chemoresistance.

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Mir-675-5p supports hypoxia-induced drug resistance in colorectal cancer cells

Cited by 13 publications

References 54 publications

MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer

MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer

Hypoxia-Inducible Factor-Dependent and Independent Mechanisms Underlying Chemoresistance of Hypoxic Cancer Cells

Long non-coding RNA H19 enhances the pro-apoptotic activity of ITF2357 (a histone deacetylase inhibitor) in colorectal cancer cells

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