Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer

Wnt5a is one of the potent signaling molecules that initiates responses involved in cancer through activation of both canonical and noncanonical signaling cascades. Wnt5a both directly and indirectly triggers cancer-associated signaling pathways based on the cancer type. In colorectal cancer (CRC), altering Wnt5a expression can influence several cellular processes of tumor cells, including proliferation, differentiation, migration, invasion, and metastasis. This review summarizes the molecular mechanisms and clinical importance of Wnt5a in the pathogenesis of CRC for better understanding the pathogenesis and its potential role as a prognostic marker and as an appropriate therapeutic target in the treatment of this disease in the future.

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Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

International Journal of Molecular Sciences ◽

10.3390/ijms222212409 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12409

Author(s):

Jelena Vekic ◽

Aleksandra Zeljkovic ◽

Aleksandra Stefanovic ◽

Rosaria Vincenza Giglio ◽

Marcello Ciaccio ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Potential Role ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Epidemiological Data ◽

Beneficial Effects ◽

Ldl Particles ◽

Chronic Hyperglycemia

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.

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Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the GNL3L and NF-κB Pathway

Cancers ◽

10.3390/cancers12051231 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1231 ◽

Cited By ~ 2

Author(s):

Thetchinamoorthy Kannathasan ◽

Wei-Wen Kuo ◽

Ming-Cheng Chen ◽

Vijaya Padma Viswanadha ◽

Chia-Yao Shen ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Tumor Volume ◽

Predictive Biomarkers ◽

Mice Model ◽

Human Colorectal Cancer ◽

Guanine Nucleotide Binding Protein ◽

Cellular Processes ◽

Nude Mice Model ◽

Guanine Nucleotide Binding

Guanine nucleotide-binding protein-like-3-like (GNL3L) is a crucial regulator of NF-κB signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of GNL3L tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of GNL3L in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence GNL3L may remarkably reduce oncogenic cell survival that depends on GNL3L/NF-κB signaling, making miR-4454 a candidate for treating metastatic human CRC.

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Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21134737 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4737 ◽

Cited By ~ 2

Author(s):

Mishghan Zehra ◽

James C. Curry ◽

Sneha S. Pillai ◽

Hari Vishal Lakhani ◽

Cory E. Edwards ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Molecular Mechanisms ◽

Potential Role ◽

Matrix Proteins ◽

Histological Evaluation ◽

Diagnostic Strategies ◽

Cellular Processes ◽

Diseased Liver ◽

Excessive Accumulation

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

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Molecular mechanisms of STIM/Orai communication

AJP Cell Physiology ◽

10.1152/ajpcell.00007.2016 ◽

2016 ◽

Vol 310 (8) ◽

pp. C643-C662 ◽

Cited By ~ 63

Author(s):

Isabella Derler ◽

Isaac Jardin ◽

Christoph Romanin

Keyword(s):

Molecular Mechanisms ◽

Signaling Cascades ◽

Signaling Cascade ◽

Cellular Processes ◽

Crac Channels ◽

Key Players ◽

Intracellular Ca ◽

Crac Channel ◽

Structural Insights ◽

Molecular Picture

Ca2+entry into the cell via store-operated Ca2+release-activated Ca2+(CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+channels open after depletion of intracellular Ca2+stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+permeation into the cell.

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Molecular mechanisms and clinical implications of miRNAs in drug resistance of colorectal cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920947342 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094734

Author(s):

Lili Duan ◽

Wanli Yang ◽

Weibo Feng ◽

Lu Cao ◽

Xiaoqian Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Molecular Mechanisms ◽

Potential Role ◽

Future Orientation ◽

Therapeutic Approaches ◽

Response To Chemotherapy ◽

Great Progress ◽

Diagnostic And Prognostic Value

Systemic chemotherapy is identified as a curative approach to prolong the survival time of patients with colorectal cancer (CRC). Although great progress in therapeutic approaches has been achieved during the last decades, drug resistance still extensively persists and serves as a major hurdle to effective anticancer therapy for CRC. The mechanism of multidrug resistance remains unclear. Recently, mounting evidence suggests that a great number of microRNAs (miRNAs) may contribute to drug resistance in CRC. Certain of these miRNAs may thus be used as promising biomarkers for predicting drug response to chemotherapy or serve as potential targets to develop personalized therapy for patients with CRC. This review mainly summarizes recent advances in miRNAs and the molecular mechanisms underlying miRNA-mediated chemoresistance in CRC. We also discuss the potential role of drug resistance-related miRNAs as potential biomarkers (diagnostic and prognostic value) and envisage the future orientation and challenges in translating the findings on miRNA-mediated chemoresistance of CRC into clinical applications.

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INFLAMMATION AND COLON CANCER. MOLECULAR AND IMMUNOLOGICAL MECHANISMS

Problems in oncology ◽

10.37469/0507-3758-2018-64-1-34-40 ◽

2018 ◽

Vol 64 (1) ◽

pp. 34-40

Author(s):

O. Kit ◽

E. Nikipelova ◽

A. Shaposhnikov ◽

E. Zlatnik ◽

I. Novikova ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Molecular Mechanisms ◽

Immune Defense ◽

Sporadic Colorectal Cancer ◽

Cancer Type ◽

Biologic Drugs ◽

Inflammatory Microenvironment ◽

Immunological Mechanisms ◽

The Impact

After the analysis of data presented in the international literature there are still a lot of controversial issues on the impact of inflammation on the development of colon cancer. Molecular mechanisms of various types of colorectal cancer are different and connected with inflammatory bowel diseases. There are some immunological similarities and differences between colitis-associated colon cancer occurring in inflammation and other types of colorectal cancer developing without any signs of inflammatory process. The gut microbiota significantly influences on the development of sporadic colorectal cancer and colitis-associated cancer. Malignant colon tumors, without dependence on the colorectal cancer type, have an increased expression of pro-inflammatory cytokines. The role of tumor-infiltrating immunocytes and tumor inflammatory microenvironment in colorectal cancer is complex: they are involved in antitumor immune defense and play a pro-oncogenic role. In perspective anti-inflammatory biologic drugs are expected to decrease the risk of the development of colorectal cancer.

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Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000490015 ◽

2018 ◽

Vol 47 (2) ◽

pp. 590-603 ◽

Cited By ~ 13

Author(s):

Xiaoting Huang ◽

Li Xiang ◽

Yueqiao Li ◽

Yingying Zhao ◽

Huiqiong Zhu ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Expression Patterns ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Invasion And Metastasis ◽

Mesenchymal Transition ◽

Expression Levels ◽

Signaling Axis

Background/Aims: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear. Methods: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo. Results: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced “CRC cell” migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis. Conclusions: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

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A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity

Frontiers in Genetics ◽

10.3389/fgene.2021.638558 ◽

2021 ◽

Vol 12 ◽

Author(s):

Saleh Almasabi ◽

Afsar U. Ahmed ◽

Richard Boyd ◽

Bryan R. G. Williams

Keyword(s):

Colorectal Cancer ◽

Immune Responses ◽

Potential Role ◽

Downstream Signaling ◽

Cellular Processes ◽

Mediator Protein ◽

Integrin Linked Kinase ◽

Inflammatory Bowel ◽

Secretory Phenotype

Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.

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