scholarly journals A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression

2021 ◽  
Vol 23 (1) ◽  
pp. 445
Author(s):  
Arka Saha ◽  
Sanith Cheriyamundath ◽  
Anmol Kumar ◽  
Nancy Gavert ◽  
Thomas Brabletz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Liver Metastasis ◽  
Cancer Progression ◽  
Colonic Mucosa ◽  
Culture Medium ◽  
Target Genes ◽  
Normal Colonic Mucosa ◽  
Cellular Processes ◽  
Colon Cancer Progression ◽  
Cell Adhesion Receptor

Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors.

scholarly journals The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression

2021 ◽  
Vol 22 (7) ◽  
pp. 3552
Author(s):  
Sanith Cheriyamundath ◽  
Anmol Kumar ◽  
Nancy Gavert ◽  
Thomas Brabletz ◽  
Avri Ben-Ze’ev
Keyword(s):  
Liver Metastasis ◽  
Cancer Progression ◽  
Cell Adhesion Molecule ◽  
Tumor Tissue ◽  
Normal Mucosa ◽  
Cell Compartment ◽  
Cellular Processes ◽  
Stem Cell Compartment ◽  
Colonic Crypts ◽  
Colon Cancer Progression

The overactivation of Wnt/b-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of b-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-kB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment.

Role of MicroRNAs in Colon Cancer Progression and Metastasis

2020 ◽  
Vol 20 ◽  
Author(s):  
Shruthi Sanjitha Sampath ◽  
Sivaramakrishnan Venkatabalsubramanian ◽  
Satish Ramalingam
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Tumour Progression ◽  
Intestinal Barrier ◽  
Colon Cancer Progression ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Novel Therapeutic Strategies

: MicroRNAs regulate gene expression at the posttranscriptional level by binding to the mRNA of their target genes. The dysfunction of miRNAs is strongly associated with the inflammation of the colon. Besides, some microRNAs are shown to suppress tumours while others promote tumour progression and metastasis. Inflammatory bowel diseases include Crohn’s disease and Ulcerative colitis which increase the risk factor for inflammation-associated colon cancer. MicroRNAs are shown to be involved in gastrointestinal pathologies, by targeting the transcripts encoding proteins of the intestinal barrier and their regulators that are associated with inflammation and colon cancer. Detection of these microRNAs in the blood, serum, tissues, faecal matter, etc will enable us to use these microRNAs as biomarkers for early detection of the associated malignancies and design novel therapeutic strategies to overcome the same. Information on MicroRNAs can be applied for the development of targeted therapies against inflammation-mediated colon cancer.

scholarly journals Identifying metastasis-initiating miRNA-target regulations of colorectal cancer from expressional changes in primary tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jongmin Lee ◽  
Hye Kyung Hong ◽  
Sheng-Bin Peng ◽  
Tae Won Kim ◽  
Woo Yong Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Mirna Target ◽  
Target Genes ◽  
Expression Profiles ◽  
Statistical Significance ◽  
Primary Tumors ◽  
Significant Difference

Abstract Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

scholarly journals An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis

2017 ◽  
Vol 16 ◽  
pp. 117693511771640 ◽  
Author(s):  
Martha L Slattery ◽  
Jennifer S Herrick ◽  
John R Stevens ◽  
Roger K Wolff ◽  
Lila E Mullany
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Colonic Mucosa ◽  
Target Gene ◽  
Target Genes ◽  
Multiple Comparisons ◽  
Normal Colonic Mucosa ◽  
Seed Region ◽  
Discovery Phase

Background: Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes. Methods: We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miRNAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations. Results: From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37, respectively. Conclusions: Our data suggest that miRNA target gene databases are incomplete; pathways derived from these databases have similar deficiencies. Although we know a lot about several miRNAs, little is known about other miRNAs in terms of their targeted genes. We encourage others to use their data to continue to further identify and validate miRNA-targeted genes.

Aberrant claudin-6–adhesion signal promotes endometrial cancer progression via estrogen receptor α

2020 ◽  
Author(s):  
Manabu Kojima ◽  
Kotaro Sugimoto ◽  
Mizuko Tanaka ◽  
Yuta Endo ◽  
Naoki Ichikawa-Tomikawa ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Endometrial Cancer ◽  
Cell Adhesion ◽  
Cancer Progression ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Estrogen Receptor Α ◽  
Aberrant Expression ◽  
Cellular Events ◽  
Human Estrogen Receptor

AbstractCell adhesion proteins not only maintain tissue integrity but also possess signaling abilities to organize diverse cellular events in physiological and pathological processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family often possesses aberrant expression in various cancers, but the biological relevance and molecular basis have not yet been established. Here, we show that high CLDN6 expression promotes endometrial cancer progression and represents the poor prognostic marker. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFKs) and to stimulate malignant phenotypes. Importantly, we demonstrate that the CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signalings target Ser518 in the human estrogen receptor α and ligand-independently activate target genes in endometrial cancer cells, resulting in cancer development. The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.

scholarly journals Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements

2020 ◽  
Vol 22 (1) ◽  
pp. 130
Author(s):  
Ahmed Malki ◽  
Rasha Abu ElRuz ◽  
Ishita Gupta ◽  
Asma Allouch ◽  
Semir Vranic ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cellular Signaling ◽  
Clinical Care ◽  
Underlying Mechanism ◽  
Cellular Mechanisms ◽  
Colon Cancer Progression ◽  
Crc Management

Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients.

scholarly journals MicroRNAs and Natural Compounds Mediated Regulation of TGF Signaling in Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeeshan Javed ◽  
Khushbukhat Khan ◽  
Amna Rasheed ◽  
Haleema Sadia ◽  
Shahid Raza ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Therapeutic Option ◽  
Natural Compounds ◽  
Male Population ◽  
Cellular Processes ◽  
Low Cytotoxicity

Prostate cancer (PCa) is with rising incidence in male population globally. It is a complex anomaly orchestrated by a plethora of cellular processes. Transforming growth factor-beta (TGF-β) signaling is one of the key signaling pathways involved in the tumorigenesis of PCa. TGF-β signaling has a dual role in the PCa, making it difficult to find a suitable therapeutic option. MicroRNAs (miRNAs) mediated regulation of TGF-β signaling is responsible for the TGF-ß paradox. These are small molecules that modulate the expression of target genes and regulate cancer progression. Thus, miRNAs interaction with different signaling cascades is of great attention for devising new diagnostic and therapeutic options for PCa. Natural compounds have been extensively studied due to their high efficacy and low cytotoxicity. Here, we discuss the involvement of TGF-ß signaling in PCa with the interplay between miRNAs and TGF-β signaling and also review the role of natural compounds for the development of new therapeutics for PCa.

scholarly journals Unraveling the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) expression in colon carcinogenesis

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Jeffrey M. Peters ◽  
Vonn Walter ◽  
Andrew D. Patterson ◽  
Frank J. Gonzalez
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Promote Cell Proliferation ◽  
Normal Tissues ◽  
Colon Cancer Progression

Abstract The peroxisome proliferator-activated-β/δ (PPARβ/δ) was identified in 1994, but not until 1999 was PPARβ/δ suggested to be involved in carcinogenesis. Initially, it was hypothesized that expression of PPARβ/δ was increased during colon cancer progression, which led to increased transcription of yet-to-be confirmed target genes that promote cell proliferation and tumorigenesis. It was also hypothesized at this time that lipid-metabolizing enzymes generated lipid metabolites that served as ligands for PPARβ/δ. These hypothetical mechanisms were attractive because they potentially explained how non-steroidal anti-inflammatory drugs inhibited tumorigenesis by potentially limiting the concentration of endogenous PPARβ/δ ligands that could activate this receptor that was increased in cancer cells. However, during the last 20 years, considerable research was undertaken describing expression of PPARβ/δ in normal and cancer cells that has led to a significant impact on the mechanisms by which PPARβ/δ functions in carcinogenesis. Whereas results from earlier studies led to much uncertainty about the role of PPARβ/δ in cancer, more recent analyses of large databases have revealed a more consistent understanding. The focus of this review is on the fundamental level of PPARβ/δ expression in normal tissues and cancerous tissue as described by studies during the past two decades and what has been delineated during this timeframe about how PPARβ/δ expression influences carcinogenesis, with an emphasis on colon cancer.

Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15093-e15093
Author(s):  
E. C. Marginean ◽  
G. Torlakovic ◽  
H. Neufeld ◽  
E. Torlakovic
Keyword(s):  
Transcription Factor ◽  
Cancer Progression ◽  
Colonic Mucosa ◽  
Colorectal Adenocarcinoma ◽  
Human Cancer ◽  
Positive Association ◽  
Experimental Models ◽  
Normal Colonic Mucosa ◽  
Chi Square ◽  
Primary Tumors

e15093 Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p<0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p<0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p<0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma. No significant financial relationships to disclose.

scholarly journals Functional analysis of tumor metastasis: modeling colon cancer

2011 ◽  
pp. 9-20
Author(s):  
Philip Y. Wai ◽  
Srinevas K. Reddy ◽  
Paul C. Kuo
Keyword(s):  
Colon Cancer ◽  
Cancer Progression ◽  
Tumor Metastasis ◽  
Target Genes ◽  
Metastatic Potential ◽  
Model Systems ◽  
Cancer Model ◽  
Poor Survival ◽  
Colon Cancer Progression ◽  
Innovative Techniques

The primary cause of death from colon cancer results from metastases that withstand conventional therapy and escape locoregional control. The molecular regulation of the tumor cell's acquired ability for invasion and metastasis is still not completely understood and progress in this field may generate novel therapeutic targets. Osteopontin (OPN) has recently been identified as a lead marker for colon cancer progression with elevated OPN expression correlating with advanced stage and poor survival. This key regulator of metastasis has been shown to induce invasive mechanisms, increase motility, adhesiveness, angiogenesis, and enhance evasion of the immune system to augment the metastatic potential in colon cancer cells. This review will discuss the basic mechanisms underlying tumor metastasis, recent innovations used to screen and identify metastatic genes in colon cancer, and model systems used to analyze these potential targets. Target genes associated with activation of OPN, a master regulator of tumor metastasis, will be described in the context of a colon cancer model. Finally, the innovative techniques of RNA interference and aptamer technology for targeting metastasis genes will be reviewed.

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