FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell

ABSTRACTCancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m6Am (N6,2’-O-dimethyladenosine) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, partially reverses this phenotype. FTO-mediated regulation of m6Am marking constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but could fine-tune translation efficiency of selected m6Am marked transcripts. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

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FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell

Nature Communications ◽

10.1038/s41467-021-21758-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sébastien Relier ◽

Julie Ripoll ◽

Hélène Guillorit ◽

Amandine Amalric ◽

Cyrinne Achour ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Messenger Rna ◽

Cancer Biology ◽

Biological Function ◽

Cancer Management ◽

Demethylase Activity

AbstractCancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N6,2’-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.

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Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis

Open Life Sciences ◽

10.1515/biol-2021-0053 ◽

2021 ◽

Vol 16 (1) ◽

pp. 523-536

Author(s):

Minghao Li ◽

Jianbin Zhuang ◽

Di Kang ◽

Yuzhuo Chen ◽

Weiliang Song

Keyword(s):

Colorectal Cancer ◽

Cancer Biology ◽

Spindle Pole ◽

Circular Rnas ◽

Cell Progression ◽

Crc Management ◽

Common Malignancy

Abstract Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been implicated in cancer biology. The purpose of the current work is to investigate the precise parts of circRNA centrosome and spindle pole-associated protein 1 (circ-CSPP1) in the progression of CRC. Our data showed that circ-CSPP1 was significantly overexpressed in CRC tissues and cells. The knockdown of circ-CSPP1 attenuated cell proliferation, migration, invasion and promoted apoptosis in vitro and weakened tumor growth in vivo. circ-CSPP1 directly targeted miR-431, and circ-CSPP1 knockdown modulated CRC cell progression in vitro via upregulating miR-431. Moreover, LIM and SH3 protein 1 (LASP1) was a functional target of miR-431 in modulating CRC cell malignant progression. Furthermore, circ-CSPP1 in CRC cells functioned as a posttranscriptional regulator on LASP1 expression by targeting miR-431. Our present study identified the oncogenic role of circ-CSPP1 in CRC partially by the modulation of the miR-431/LASP1 axis, providing evidence for circ-CSPP1 as a promising biomarker for CRC management.

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MicroRNA: Promising Roles in Cancer Therapy

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200420101613 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1186-1203

Author(s):

Atieh Hashemi ◽

Gilar Gorji-bahri

Keyword(s):

Cancer Therapy ◽

Cancer Biology ◽

Tumor Regression ◽

Target Cells ◽

Cancer Management ◽

Efficient Delivery ◽

Chemotherapy Agents

MicroRNAs (miRNA) are small non-coding RNAs that act as one of the main regulators of gene expression. They are involved in maintaining a proper balance of diverse processes, including differentiation, proliferation, and cell death in normal cells. Cancer biology can also be affected by these molecules by modulating the expression of oncogenes or tumor suppressor genes. Thus, miRNA based anticancer therapy is currently being developed either alone or in combination with chemotherapy agents used in cancer management, aiming at promoting tumor regression and increasing cure rate. Access to large quantities of RNA agents can facilitate RNA research and development. In addition to currently used in vitro methods, fermentation-based approaches have recently been developed, which can cost‐effectively produce biological RNA agents with proper folding needed for the development of RNA-based therapeutics. Nevertheless, a major challenge in translating preclinical studies to clinical for miRNA-based cancer therapy is the efficient delivery of these agents to target cells. Targeting miRNAs/anti-miRNAs using antibodies and/or peptides can minimize cellular and systemic toxicity. Here, we provide a brief review of miRNA in the following aspects: biogenesis and mechanism of action of miRNAs, the role of miRNAs in cancer as tumor suppressors or oncogenes, the potential of using miRNAs as novel and promising therapeutics, miRNA-mediated chemo-sensitization, and currently utilized methods for the in vitro and in vivo production of RNA agents. Finally, an update on the viral and non-viral delivery systems is addressed.

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WD40 Repeat 43 Mediates Cell Survival, Proliferation, Migration and Invasion via Vimentin in Colorectal Cancer

10.21203/rs.3.rs-269248/v1 ◽

2021 ◽

Author(s):

Zijian Li ◽

Min Feng ◽

Jie Zhang ◽

Xingzhou Wang ◽

En Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Biological Function ◽

Xenograft Model ◽

Migration And Invasion ◽

Clinical Samples ◽

Subcutaneous Xenograft

Abstract BackgroundWD40 repeat (WDR)43 is an RNA-binding protein that belongs to the WDR domain protein family. Its biological function is largely unclear, particularly in colorectal cancer (CRC). MethodsIn the present study, we searched the TCGA database and found the correlation between WDR43 and CRC. Subsequently,the high expression of WDR43 in human clinical samples of CRC was validated and we further examined the biological functions of it in CRC cells.Finally,we explored potential downstream proteins or pathways and established subcutaneous xenograft model to verify our findings.ResultsImmunohistochemistry of 16 patient specimens confirmed that the expression of WDR43 was elevated in CRC. WDR43 knockdown was shown to increase apoptosis and inhibit the proliferation, migration and invasion of CRC cells in vitro and reduce tumorigenesis in animal models.In addition, it was found that WDR43 knockdown inhibited vimentin (VIM) expression in CRC cells and overexpression of VIM can partially reverse the effects of WDR43 both in vitro and in vivo. ConclusionIn conclusion, the role of WDR43 in the occurrence and development of CRC was investigated in the present study. WDR43 may serve as a valuable biomarker and provide new options for the diagnosis and treatment of colorectal cancer.

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Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01882-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Zizhen Si ◽

Lei Yu ◽

Haoyu Jing ◽

Lun Wu ◽

Xidi Wang

Keyword(s):

Colorectal Cancer ◽

Rna Binding ◽

Xenograft Model ◽

Luciferase Reporter ◽

Cancer Proliferation ◽

Mouse Xenograft ◽

Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

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YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

Cell Death and Disease ◽

10.1038/s41419-021-03722-8 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Lan Jin ◽

Yunhe Chen ◽

Dan Cheng ◽

Zhikai He ◽

Xinyi Shi ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Transcriptional Coactivator ◽

Inhibitory Protein ◽

Potential Therapeutic Target ◽

Related Cell ◽

Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

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The lncRNA XIST promotes colorectal cancer cell growth through regulating the miR-497-5p/FOXK1 axis

Cancer Cell International ◽

10.1186/s12935-020-01647-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Nan Wang ◽

Jia-Xing He ◽

Guo-Zhan Jia ◽

Ke Wang ◽

Shuai Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Cancer Cell Growth ◽

Forkhead Box ◽

Proliferation And Apoptosis ◽

Lncrna Xist

Abstract Background Recent studies suggest that long noncoding RNAs (lncRNAs) play an important role in tumorigenesis. As a newly identified lncRNA, the role of XIST in colorectal cancer (CRC) has not been established. Here, we sought to characterize the role of XIST and its associated regulatory network in CRC cells. Methods Expression of XIST mRNA, miR-497-5p, and forkhead box k1 (FOXK1) in CRC cells and tissues were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Proliferation and apoptosis of CRC cells were determined using the CCK-8 cell counting assay and flow cytometry. The rate of cell migration and invasion was determined using a transwell assay. The relationships between XIST, miR-497-5p, and FOXK1 were predicted and confirmed using a dual-luciferase reporter assay. Expression of FOXK1 protein was quantified by Western blot. Results XIST and FOXK1 expression were significantly upregulated in CRC tissues and cell lines, while miR-497-5p expression was downregulated. XIST knockdown significantly suppressed CRC cell proliferation, migration, and invasion. Silencing of XIST also reversed the downregulation of miR-497-5p and upregulation of FOXK1. Moreover, blocking XIST expression was shown to inhibit CRC tumor growth in vivo and the effects were antagonized by the loss of miR-497-5p. miR-497-5p was shown to act as a sponge of XIST and also targeted FOXK1 in CRC cells. Conclusions XIST was shown to promote the malignancy of CRC cells by competitively binding to miR-497-5p, resulting in an increase in FOXK1 expression. These results suggest that targeting of XIST may represent a possible treatment for CRC.

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Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Cancers ◽

10.3390/cancers12030765 ◽

2020 ◽

Vol 12 (3) ◽

pp. 765 ◽

Cited By ~ 4

Author(s):

Kamila Pawlicka ◽

Umesh Kalathiya ◽

Javier Alfaro

Keyword(s):

Messenger Rna ◽

Mrna Decay ◽

Tumour Progression ◽

Transcript Abundance ◽

Tumour Suppressor Genes ◽

Nonsense Mediated Mrna Decay ◽

The Many ◽

Cycle Regulation ◽

Fine Tune

Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases.

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The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

International Journal of Molecular Sciences ◽

10.3390/ijms19123711 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3711 ◽

Cited By ~ 22

Author(s):

Ovidiu Balacescu ◽

Daniel Sur ◽

Calin Cainap ◽

Simona Visan ◽

Daniel Cruceriu ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Cancer Progression ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Cancer Management ◽

Incidence And Mortality ◽

The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

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A Novel Lactic Acid Bacteria Mixture: Macrophage-Targeted Prophylactic Intervention in Colorectal Cancer Management

Microorganisms ◽

10.3390/microorganisms8030387 ◽

2020 ◽

Vol 8 (3) ◽

pp. 387

Author(s):

Petra Hradicka ◽

Jane Beal ◽

Monika Kassayova ◽

Andrew Foey ◽

Vlasta Demeckova

Keyword(s):

Colorectal Cancer ◽

Male Rats ◽

Cancer Management ◽

Immune Parameters ◽

Chemically Induced ◽

Tnf Α ◽

Vitro Model ◽

Macrophage Subsets

Colorectal cancer (CRC) is one of the most common forms of cancer. Its onset from chronic inflammation is widely accepted. Moreover, dysbiosis plays an undeniable role, thus the use of probiotics in CRC has been suggested. They exhibit both anti- and pro-inflammatory properties and restore balance in the microbiota. The aim of this study was to investigate the immunomodulatory properties of six lactobacilli with probiotic features in an in vitro model of macrophage-like cells and to test these pooled probiotics for their anti-tumour properties in a chemically induced CRC model using Wistar male rats. Upon co-culture of M1- and M2-like macrophages with lactobacilli, cytokine release (TNF-α, IL-1β, IL-18, IL-23) and phagocytic activity using fluorescent-labelled bacteria were tested. The effects of orally administered probiotics on basic cancer and immune parameters and cytokine concentration (TNF-α, IL-1β, IL-18) in colon tumours were studied. Tested lactobacilli exhibited both pro- and anti-inflammatory properties in in vitro conditions. In vivo study showed that the administration of probiotics was able to decrease multiplicity, volume and total tumour numbers, restore colon length (p < 0.05) and increase IL-18 production (p < 0.05) in tumour tissue. These data indicate both an immunomodulatory effect of probiotics on distinct macrophage subsets and a protective effect against chemically-induced CRC.

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