The Impact of Diet on the Involvement of Non-Coding RNAs, Extracellular Vesicles, and Gut Microbiome-Virome in Colorectal Cancer Initiation and Progression

Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.

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Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer

Current Treatment Options in Oncology ◽

10.1007/s11864-021-00870-z ◽

2021 ◽

Vol 22 (8) ◽

Author(s):

Federica Pecci ◽

Luca Cantini ◽

Alessandro Bittoni ◽

Edoardo Lenci ◽

Alessio Lupi ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Progression ◽

Checkpoint Inhibitors ◽

Tnm Classification ◽

Standard Of Care ◽

First Line Therapy ◽

Combination Strategies ◽

The Impact

Opinion statementAdvanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An “immunoscore,” based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

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PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment

Cell Death and Disease ◽

10.1038/s41419-021-03914-2 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Guangyu Ji ◽

Wenjuan Zhou ◽

Jingyi Du ◽

Juan Zhou ◽

Dong Wu ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Tumour Progression ◽

Stem Cell Markers ◽

Epigenetic Regulator ◽

Cell Enrichment ◽

Histone Trimethylation

AbstractColorectal cancer (CRC) stem cells are resistant to cancer therapy and are therefore responsible for tumour progression after conventional therapy fails. However, the molecular mechanisms underlying the maintenance of stemness are poorly understood. In this study, we identified PCGF1 as a crucial epigenetic regulator that sustains the stem cell-like phenotype of CRC. PCGF1 expression was increased in CRC and was significantly correlated with cancer progression and poor prognosis in CRC patients. PCGF1 knockdown inhibited CRC stem cell proliferation and CRC stem cell enrichment. Importantly, PCGF1 silencing impaired tumour growth in vivo. Mechanistically, PCGF1 bound to the promoters of CRC stem cell markers and activated their transcription by increasing the H3K4 histone trimethylation (H3K4me3) marks and decreasing the H3K27 histone trimethylation (H3K27me3) marks on their promoters by increasing expression of the H3K4me3 methyltransferase KMT2A and the H3K27me3 demethylase KDM6A. Our findings suggest that PCGF1 is a potential therapeutic target for CRC treatment.

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Cyst(e)ine in nutrition formulation promotes colon cancer growth and chemoresistance by activating mTORC1 and scavenging ROS

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00581-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jiao Wu ◽

Sai-Ching Jim Yeung ◽

Sicheng Liu ◽

Aiham Qdaisat ◽

Dewei Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Weight Loss ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Progression ◽

Colorectal Cancer Patient ◽

Nutrition Support ◽

Immunodeficient Mice ◽

The Impact

AbstractWeight loss and cachexia are common problems in colorectal cancer patients; thus, parenteral and enteral nutrition support play important roles in cancer care. However, the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied. In this study, we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival (P < 0.001) than those who did not. Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice, predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis, resulting in mTORC1 activation. mTORC1 inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation. In addition, cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione. We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin. These findings indicate that cyst(e)ine, as part of supplemental nutrition, plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.

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A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-09958-2 ◽

2021 ◽

Author(s):

Victor Delprat ◽

Carine Michiels

Keyword(s):

Tumor Progression ◽

Cancer Progression ◽

Cell Activation ◽

Molecular Mechanisms ◽

Immune Cell ◽

The Body ◽

Vascular Cells ◽

Tumor Associated Macrophage ◽

Immune Cell Activation ◽

The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

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Circ-GALNT16 Restrains Colorectal Cancer Progression by Enhancing the SUMOylation of hnRNPK

10.21203/rs.3.rs-501100/v1 ◽

2021 ◽

Author(s):

Chaofan Peng ◽

Yuqian Tan ◽

Peng Yang ◽

Kangpeng Jin ◽

Chuan Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Binding ◽

Rna Sequencing ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Transcriptional Level ◽

Multiple Cancer ◽

Binding Ability ◽

Colorectal Cancer Progression

Abstract BackgroundEmerging studies have investigated circRNAs as significant regulation factors in multiple cancer progression. Nevertheless, the biological functions and underlying mechanisms of circRNAs in colorectal cancer progression remain unclear.MethodsA novel circRNA (circ-GALNT16) was identified by microarray and qRT-PCR. A series of phenotype experiments in vitro and vivo were performed to investigate the role of circ-GALNT16 in CRC. FISH, RNA pulldown assay, RIP assay, RNA sequencing, coimmunoprecipitation, and ChIP were constructed to explore the molecular mechanisms of circ-GALNT16 in colorectal cancer.ResultsCirc-GALNT16 was downregulated in colorectal cancer and negatively correlated with poor prognosis. Circ-GALNT16 suppressed the proliferation and metastasis ability of colorectal cancer in vitro and vivo. Mechanistically, circ-GALNT16 could bind to the KH3 domain of heterogeneous nuclear ribonucleoprotein K (hnRNPK), which resulted in the SUMOylation of hnRNPK. Additionally, circ-GALNT16 could enhance the hnRNPK-p53 complex by facilitating the SUMOylation of hnRNPK. Furthermore, RNA sequencing assay identified serpin family E member 1 as the target gene of circ-GALNT16 at the transcriptional level. Rescue assays revealed that circ-GALNT16 regulated the expression of Serpine1 by inhibiting the deSUMOylation of hnRNPK mediated by SUMO specific peptidase 2 and then regulating the sequence-specific DNA binding ability of the hnRNPK-p53 transcriptional complex.ConclusionsCirc-GALNT16 suppressed CRC progression via inhibiting Serpine1 expression through adjusting the sequence-specific DNA binding ability of the SENP2-mediated hnRNPK-p53 transcriptional complex and might work as a biomarker and therapeutic target for CRC.

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DLX6-AS1: a putative lncRNA candidate in multiple human cancers

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2021.17 ◽

2021 ◽

Vol 23 ◽

Author(s):

Mohsen Sheykhhasan ◽

Yaghoub Ahmadyousefi ◽

Reihaneh Seyedebrahimi ◽

Hamid Tanzadehpanah ◽

Hamed Manoochehri ◽

...

Keyword(s):

Cancer Progression ◽

Critical Analysis ◽

Molecular Mechanisms ◽

Signalling Pathways ◽

Biological Functions ◽

Initial Development ◽

Human Cancers ◽

Expression Of Genes ◽

Non Coding Rnas ◽

Research Studies

Abstract Long non-coding RNAs (lncRNAs) have important roles in regulating the expression of genes and act as biomarkers in the initial development of different cancers. Increasing research studies have verified that dysregulation of lncRNAs occurs in various pathological processes including tumorigenesis and cancer progression. Among the different lncRNAs, DLX6-AS1 has been reported to act as an oncogene in the development and prognoses of different cancers, by affecting many different signalling pathways. This review summarises and analyses the recent research studies describing the biological functions of DLX6-AS1, its overall effect on signalling pathways and the molecular mechanisms underlying its action on the expression of genes in multiple human cancers. Our critical analysis suggests that different signalling pathways associated to this lncRNA may be used as a biomarker for diagnosis, or targets of treatment in cancers.

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The effective function of circular RNA in colorectal cancer

Cancer Cell International ◽

10.1186/s12935-021-02196-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mandana Ameli-Mojarad ◽

Melika Ameli-Mojarad ◽

Mahrooyeh Hadizadeh ◽

Chris Young ◽

Hosna Babini ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rna ◽

Circular Rnas ◽

Colorectal Tumorigenesis ◽

Non Coding Rnas ◽

Mirna Sponges ◽

Mechanisms Of Development

AbstractColorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late detection plays role in one-third of annual mortality due to CRC. Therefore, it is essential to find a precise and optimal diagnostic and prognostic biomarker for the identification and treatment of colorectal tumorigenesis. Covalently closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have the same function as microRNA (miRNA) sponges, as regulators of splicing and transcription, and as interactors with RNA-binding proteins (RBPs). Therefore, circRNAs have been investigated as specific targets for diagnostic and prognostic detection of CRC. These non-coding RNAs are also linked to metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis, and drug resistance, illustrating the importance of understanding their involvement in the molecular mechanisms of development and progression of CRC. In this review, we present a detailed summary of recent findings relating to the dysregulation of circRNAs and their potential role in CRC.

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Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

Bioscience Reports ◽

10.1042/bsr20191488 ◽

2020 ◽

Vol 40 (1) ◽

Author(s):

Guosen Wang ◽

Weiwei Sheng ◽

Jingtong Tang ◽

Xin Li ◽

Jianping Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Migration And Invasion ◽

Chemical Agent ◽

Cell Migration And Invasion ◽

Agent Treatment ◽

Hct116 Cells

Abstract Serine-arginine protein kinase 2 (SRPK2) is aberrantly expressed in human malignancies including colorectal cancer (CRC). However, little is known about the molecular mechanisms, and the role of SRPK2 in chemosensitivity remains unexplored in CRC. We recently showed that SRPK2 promotes pancreatic cancer progression by down-regulating Numb and p53. Therefore, we investigated the cooperation between SRPK2, Numb and p53 in the cell migration, invasion and chemosensitivity of CRC in vitro. Here, we showed that SRPK2 expression was higher in CRC tumors than in nontumor tissues. SRPK2 expression was positively associated with clinicopathological characteristics of CRC patients, including tumor differentiation, T stage, N stage and UICC stage. Additionally, SRPK2 had no association with mutant p53 (mtp53) in SW480 and SW620 cells, but negatively regulated Numb and wild-type p53 (wtp53) in response to 5-fluorouracil or cisplatin treatment in HCT116 cells. Moreover, SRPK2, Numb and p53 coimmunoprecipitated into a triple complex with or without the treatment of 5-fluorouracil in HCT116 cells, and p53 knockdown reversed the up-regulation of wtp53 induced by SRPK2 silencing with chemical agent treatment. Furthermore, overexpression of SRPK2 increased cell migration and invasion and decreased chemosensitivity to 5-fluorouracil or cisplatin in HCT116 cells. Conversely, SRPK2 silencing decreased cell migration and invasion and increased chemosensitivity to 5-fluorouracil or cisplatin, yet these effects could be reversed by p53 knockdown under chemical agent treatment. These results thus reveal a novel role of SRPK2-Numb-p53 signaling in the progression of CRC and demonstrate that SRPK2 is a potential therapeutic target for CRC clinical therapy.

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miR-224 targets BTRC and promotes cell migration and invasion in colorectal cancer

3 Biotech ◽

10.1007/s13205-020-02477-x ◽

2020 ◽

Vol 10 (11) ◽

Author(s):

Qi Zheng ◽

Jane J. Yu ◽

Chenggang Li ◽

Jiali Li ◽

Jiping Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Migration ◽

Protein Expression ◽

Molecular Mechanisms ◽

Early Stage ◽

Luciferase Assay ◽

Migration And Invasion ◽

Cell Migration And Invasion ◽

Normal Tissues ◽

The Impact

AbstractOur study aims to investigate the impact of miR-224 on cell migration and invasion in colorectal cancer (CRC) as well as its molecular mechanisms. The results showed that miR-224 was significantly upregulated in CRC compared to normal tissues via the TCGA database. Overexpression of miR-224 promoted CRC cell migration and invasion, while inhibition of miR-224 demonstrated the opposite result via transwell assays. In addition, we found that BTRC was a target gene of miR-224 through the miRecords database and dual-luciferase assay, while western blot together with RT-qPCR showed that inhibition of miR-224 led to elevated BTRC expression in protein level but not in mRNA level, and also decreased the expression of β-catenin. In reference to the Human Protein Atlas, BTRC protein expression was higher in normal tissues than in CRC tissues. In conclusion, miR-224 regulates its target BTRC protein expression and its related Wnt/β-catenin pathway. Its impact on cell migration and invasion in CRC cells suggested that miR-224 could be a prospective therapeutic target for early-stage non-metastatic CRC.

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