Is Metformin a Therapeutic Paradigm for Colorectal Cancer: Insight into the Molecular Pathway?

Bacteriophages are the most prominent members of the gut microbiome, outnumbering their bacterial hosts by a factor of 10. Phages are bacteria-specific viruses that are gaining attention as highly influential regulators of the gut bacterial community. Dysregulation of the gut bacterial community contributes to dysbiosis, a microbiome disorder characterized by compositional and functional changes that contribute to disease. A role for phages in gut microbiome dysbiosis is emerging with evidence that the gut phage community is altered in dysbiosis-associated disorders such as colorectal cancer and inflammatory bowel disease. Several recent studies have linked successful fecal microbiota transplantation to uptake of the donor’s gut phage community, offering some insight into why some recipients respond to treatment whereas others do not. Here, we review the literature supporting a role for phages in mediating the gut bacterial community, giving special attention to Western diet dysbiosis as a case study to demonstrate a theoretical phage-based mechanism for the establishment and maintenance of dysbiosis.

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The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how nonconserved residues dictate its function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902211116 ◽

2019 ◽

Vol 116 (41) ◽

pp. 20404-20410 ◽

Cited By ~ 7

Author(s):

Amy J. Fernandez ◽

Earnest James Paul Daniel ◽

Sai Pooja Mahajan ◽

Jeffrey J. Gray ◽

Thomas A. Gerken ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Basis ◽

Catalytic Domain ◽

Binding Pocket ◽

Substrate Selectivity ◽

Peptide Substrate ◽

X Ray ◽

Biochemical Studies ◽

Cancer Mutations ◽

Insight Into

Polypeptide N-acetylgalactosaminyl transferases (GalNAc-Ts) initiate mucin type O-glycosylation by catalyzing the transfer of N-acetylgalactosamine (GalNAc) to Ser or Thr on a protein substrate. Inactive and partially active variants of the isoenzyme GalNAc-T12 are present in subsets of patients with colorectal cancer, and several of these variants alter nonconserved residues with unknown functions. While previous biochemical studies have demonstrated that GalNAc-T12 selects for peptide and glycopeptide substrates through unique interactions with its catalytic and lectin domains, the molecular basis for this distinct substrate selectivity remains elusive. Here we examine the molecular basis of the activity and substrate selectivity of GalNAc-T12. The X-ray crystal structure of GalNAc-T12 in complex with a di-glycosylated peptide substrate reveals how a nonconserved GalNAc binding pocket in the GalNAc-T12 catalytic domain dictates its unique substrate selectivity. In addition, the structure provides insight into how colorectal cancer mutations disrupt the activity of GalNAc-T12 and illustrates how the rules dictating GalNAc-T12 function are distinct from those for other GalNAc-Ts.

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Correction to: Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer

Human Genetics ◽

10.1007/s00439-019-02030-8 ◽

2019 ◽

Vol 138 (7) ◽

pp. 789-791

Author(s):

Stephanie A. Bien ◽

Yu-Ru Su ◽

David V. Conti ◽

Tabitha A. Harrison ◽

Conghui Qu ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Genetic Variant ◽

Insight Into

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Insight Into the Role of the General Practitioner in the Management of Colorectal Cancer: Record Linkage of the Netherlands Cancer Registry and the General Practitioner Database of the Pharmo Database Network

Value in Health ◽

10.1016/j.jval.2017.08.2049 ◽

2017 ◽

Vol 20 (9) ◽

pp. A741 ◽

Cited By ~ 1

Author(s):

JG Kuiper ◽

MP van Herk-Sukel ◽

VE Lemmens ◽

R van Wijngaarden ◽

RM Herings

Keyword(s):

Colorectal Cancer ◽

General Practitioner ◽

The Netherlands ◽

Cancer Registry ◽

Record Linkage ◽

Netherlands Cancer Registry ◽

Insight Into

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Genome edited colorectal cancer organoid models reveal distinct microRNA activity patterns across different mutation profiles

10.1101/2021.12.13.472432 ◽

2021 ◽

Author(s):

Jonathan W Villanueva ◽

Lawrence Kwong ◽

Teng Han ◽

Salvador Alonso Martinez ◽

Fong Cheng Pan ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Genetically Modified ◽

Activity Patterns ◽

Expression Patterns ◽

Regulatory Mechanisms ◽

Oncogenic Mutations ◽

Gene Regulatory ◽

Insight Into

Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect microRNAs. Here, using genetically-modified mouse intestinal organoid (enteroid) models, we identify ten different modules of microRNA expression patterns across distinct combinations of mutations common in CRC. We also show that miR-24-3p, which is aberrant in genetically-modified mouse enteroids and human colonoids irrespective of mutational context, is a master regulator of gene expression in CRC. In follow-up experiments, we also demonstrate that miR-24 promotes CRC cell survival. These findings offer insight into the mechanisms that drive inter-tumor heterogeneity and highlight candidate microRNA therapeutic targets for the advancement of precision medicine for CRC.

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miR-539 activates the SAPK/JNK signaling pathway to promote ferropotosis in colorectal cancer by directly targeting TIPE

Cell Death Discovery ◽

10.1038/s41420-021-00659-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yan Yang ◽

Zeyang Lin ◽

Zhaopu Han ◽

Zhengxin Wu ◽

Jianyu Hua ◽

...

Keyword(s):

Colorectal Cancer ◽

High Recurrence Rate ◽

The Novel ◽

Potential Therapeutic Target ◽

Tnf Α ◽

Jnk Signaling Pathway ◽

The Relationship ◽

Insight Into ◽

Necrosis Factor

AbstractColorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential therapeutic target for advanced CRC.

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