Role of SA1 Polymorphisms in Metabolic Reprogramming in Colorectal Cancer: Implications for Racial Disparities

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one of the important cancer hallmarks in CRC, which involves the adaptive changes in tumour cell metabolism to sustain the high energy requirements for rapid cell proliferation. There are several mechanisms in the metabolic reprogramming of cancer cells, such as aerobic glycolysis, oxidative phosphorylation, lactate and fatty acids metabolism. MicroRNAs (miRNAs) are a class of non-coding RNAs that are responsible for post-transcriptional regulation of gene expression. Differential expression of miRNAs has been shown to play an important role in different aspects of tumorigenesis, such as proliferation, apoptosis, and drug resistance, as well as metabolic reprogramming. Increasing evidence also reports that miRNAs could function as potential regulators of metabolic reprogramming in CRC cells. This review provides an insight into the role of different miRNAs in regulating the metabolism of CRC cells as well as to discuss the potential role of miRNAs as biomarkers or therapeutic targets in CRC tumour metabolism.

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Racial Disparities in Colorectal Cancer Mortality: the Role of Endoscopy Wait-Time and Stage at Diagnosis

Journal of Racial and Ethnic Health Disparities ◽

10.1007/s40615-020-00721-x ◽

2020 ◽

Vol 7 (5) ◽

pp. 967-974

Author(s):

Rachel B. Issaka ◽

Li Li ◽

Catherine Fedorenko ◽

Cynthia W. Ko ◽

John M. Inadomi ◽

...

Keyword(s):

Colorectal Cancer ◽

Racial Disparities ◽

Cancer Mortality ◽

Wait Time ◽

Stage At Diagnosis ◽

Colorectal Cancer Mortality

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Aberrant SLC6A14 Expression Promotes Proliferation and Metastasis of Colorectal Cancer Via Enhancing the JAK2/STAT3 Pathway

10.21203/rs.3.rs-70361/v1 ◽

2020 ◽

Author(s):

Hongli Mao ◽

Jinxiu Sheng ◽

Jinlin Jia ◽

Chang Wang ◽

Shanfeng Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Mammalian Cells ◽

Metabolic Reprogramming ◽

Cell Counting ◽

Migration And Invasion ◽

Advanced Tumor Stage ◽

Stat3 Signaling

Abstract Background: Solute carrier family 6 member 14 (SLC6A14) is a high-capacity amino acid transporter in mammalian cells. It has gained increasing attention for its potential involvement in the progression and metabolic reprogramming of various malignant tumors. However, the role of SLC6A14 in colorectal cancer (CRC) remains unclear. Methods: Real-time polymerase chain reaction (qRT-PCR), immunoblotting and immunohistochemistry were carried out to detect the expression level of SLC6A14 in human CRC tissues and CRC-derived cell lines. HCT-116 and Caco-2 cell lines were selected to conduct the in vitro functional studies. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, cell migration and invasion assays were performed to investigate the role of SLC6A14 in CRC cells. Besides, Azoxymethane/Dextran Sulfate Sodium Salt (AOM/DSS)-induced CRC and tumor xenograft models were constructed to explore the effects of SLC6A14 blockade or overexpression on tumor progression in vivo. Results: SLC6A14 was substantially increased in human CRC samples and higher levels of SLC6A14 was correlated with advanced tumor stage, lymph node metastasis and dismal survival of CRC patients. SLC6A14 markedly promoted cell growth, inhibited cell apoptosis, exacerbated migration and invasion of CRC cells in vitro. Mechanistically, SLC6A14 aggravated these malignant phenotypes through activating JAK2/STAT3 signaling pathway, and inhibiting JAK2/STAT3 signaling with specific inhibitors could reverse SLC6A14-mediated tumorigenic effects. Besides, two different animal studies verified the tumor-promoting effect of SLC6A14 in CRC. Conclusion: Our data illustrated the crucial function that SLC6A14 played in the promotion of CRC, suggesting SLC6A14/JAK2/STAT3 axis may serve as novel therapeutic targets for patients with CRC.

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Cancer-Secreted Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis By Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts

10.21203/rs.3.rs-708870/v1 ◽

2021 ◽

Author(s):

Chong Zhang ◽

Xiang-Yu Wang ◽

Peng Zhang ◽

Tao-Chen He ◽

Jia-Hao Han ◽

...

Keyword(s):

Colorectal Cancer ◽

Lipid Metabolism ◽

Liver Metastasis ◽

Metabolic Reprogramming ◽

Regulation Mechanism ◽

Dependent Manner ◽

Cancer Associated Fibroblasts ◽

Metastatic Niche

Abstract Background: Metastasis and metabolic deregulation are two of the major hallmarks of cancer. Recent studies have revealed the critical driving role of metabolic reprogramming of tumor cells to promote colorectal cancer (CRC) metastasis. However, little is known about the metabolic alterations of cancer-associated fibroblasts (CAFs) in the pre-metastatic niche and how these changes facilitate CRC metastasis.Methods: Liquid chromatography-mass spectrometry (LC-MS) and Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the comparative metabolites and proteins expression in CAFs treated with exosomes derived from CRC cells, respectively. Tissue Microarray (TMA) was used to evaluate the level of HSPC111 in patient’s primary CRC tissues with or without liver metastasis. Co-immunoprecipitation (Co-IP), RNA-seq, chromatin immunoprecipitation (ChIP) migration and wound healing assay and immunofluorescence staining were employed to explore the expression regulation mechanism of exosomal HSPC111 in CAFs. Xenograft models were used to determine whether exosomal HSPC111 can remolding pre-metastatic niche of CAFs to promote CRC liver metastasis (CRLM) in vivo.Results: Here, we demonstrate that CRC cell-secreted exosomal HSPC111 induces a lipid metabolism reprogramming process in CAFs. Importantly, our results indicate that CRC patients with liver metastasis had significantly high level of HSPC111 in CRC tissues than CRC patients without liver metastasis. Mechanistically, HSPC111 upregulate the level of acetyl-CoA and histone acetylation by phosphorylating of ATP-citrate lyase (ACLY) in CAFs. This lipid metabolism reprogramming in CAFs facilitates CXCL5 secretion in vitro and pre-metastatic niche formation in the liver to promote CRLM in an exosomal HSPC111-dependent manner in vivo. In addition, conditioned medium (CM) from CAFs induce EMT of CRC cells by down-regulating E-cadherin levels and up-regulating Vimentin and Snail levels, which could be abolished by CXCL5-neutralizing antibody and CXCR2 inhibitor navarixin. Moreover, the HSPC111-ACLY association in CAFs was reinforced by CXCL5-CXCR2 axis, further promoting exosomal HSPC111 secretion from CRC cells to form a feedforward regulatory loop.Conclusion: Our present study reveals a novel insight into the pro-metastatic role of lipid metabolism reprogramming in CAFs and suggests the CXCL5-CXCR2 axis may be a promising target for halting CRLM.

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Sa1022 – Racial Disparities in Colorectal Cancer Mortality: the Role of Endoscopy Wait-Time and Disease Stage

Gastroenterology ◽

10.1016/s0016-5085(19)37449-9 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-258

Author(s):

Rachel B. Issaka ◽

Li Li ◽

Catherine Fedorenko ◽

Cynthia W. Ko ◽

John M. Inadomi ◽

...

Keyword(s):

Colorectal Cancer ◽

Racial Disparities ◽

Cancer Mortality ◽

Wait Time ◽

Disease Stage ◽

Colorectal Cancer Mortality

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The Contemporary Role of Resection and Ablation in Colorectal Cancer Liver Metastases

Digestive Disease Interventions ◽

10.1055/s-0040-1715816 ◽

2020 ◽

Vol 04 (03) ◽

pp. 291-302

Author(s):

Mariam F. Eskander ◽

Christopher T. Aquina ◽

Aslam Ejaz ◽

Timothy M. Pawlik

Keyword(s):

Colorectal Cancer ◽

Portal Vein ◽

Surgical Oncology ◽

Portal Vein Ligation ◽

Safe Alternative ◽

Colorectal Cancer Liver Metastases ◽

Liver Remnant ◽

New Era ◽

Ablation Therapy

AbstractAdvances in the field of surgical oncology have turned metastatic colorectal cancer of the liver from a lethal disease to a chronic disease and have ushered in a new era of multimodal therapy for this challenging illness. A better understanding of tumor behavior and more effective systemic therapy have led to the increased use of neoadjuvant therapy. Surgical resection remains the gold standard for treatment but without the size, distribution, and margin restrictions of the past. Lesions are considered resectable if they can safely be removed with tumor-free margins and a sufficient liver remnant. Minimally invasive liver resections are a safe alternative to open surgery and may offer some advantages. Techniques such as portal vein embolization, association of liver partition with portal vein ligation for staged hepatectomy, and radioembolization can be used to grow the liver remnant and allow for resection. If resection is not possible, nonresectional ablation therapy, including radiofrequency and microwave ablation, can be performed alone or in conjunction with resection. This article presents the most up-to-date literature on resection and ablation, with a discussion of current controversies and future directions.

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