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Molecular Mechanisms and Therapies of Colorectal Cancer
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Molecular Mechanisms and Therapies of Colorectal Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 36848

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Donatella Delle Cave

E-Mail Website
Guest Editor
Institute of Genetics and Biophysics "A. Buzzati Traverso" (IGB-ABT), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: pancreatic cancer; cancer stem cells; tumor microenvironment; cancer metabolism; fibrosis; TGF-β signaling; target therapy; drug delivery systems
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandro Ottaiano

E-Mail Website
Guest Editor
Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”, Via M. Semmola, 80131 Naples, Italy
Interests: abdominal cancers; colorectal cancer; immunotherapy; genomic landscape; neuroendocrine tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality. Transforming growth factor beta (TGF-β) signaling have been associated with CRC growth and metastasis, due to its involvement in proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis. TGF-β superfamily contains over forty members, including TGF-βs, Nodal, Activin, and bone morphogenetic proteins (BMPs). Three types of TGF-β receptors (TGFβR) have been identified: type 1, 2 and 3. After ligand binding, TGF-βR2 recruits and phosphorylates TGF-βR1 that in turn phosphorylates downstream SMAD (small mother against decapentaplegic) proteins. Phosphorylated SMAD4 translocates into the nucleus where it activates transcription of numerous target genes (including SERPINE1, LTBP2, CDKN1A, ARID3B, ATXN1, PTPRK, RAB6A, SMAD7, EHBP1, etc.) acting predominantly as a tumor-suppressor gene. Interestingly, alterations of SMAD4 are frequent in metastatic CRC and, together with TGF-βR2 genes mutations, have been reported as late events able to promote CRC progression. The study of TGF-β pathway in metastatic CRC is challenging because of great genetic heterogeneity of CRC. However, the increasing availability of targeted and whole exome DNA sequencing techniques make possible to identify genes' mutations in complex, dynamic and heterogeneous clinical contexts and to make correlations with clinical outcome.

This Special Issue was established to prompt researchers to perform studies on:

  • Involvement of TGF-β pathway in metastatic CRC.
  • Emerging methods to identify and correlate specific TGF-β pathway genes' mutations with metastatic behavior.
  • Novel approaches to target TGF-β pathway in metastatic CRC.
  • Novel studies to depict TGF-β pathway evolution from primary to metastatic lesions.

Articles consisting exclusively of bioinformatics or computational analyses of public databases or pure clinical studies will not be accepted. Basic studies or translational studies including molecular characterizations of patients from real practice are welcome. Reviews are also appreciated


Dr. Donatella Delle Cave
Prof. Dr. Alessandro Ottaiano
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Transforming growth factor beta (TGF-β) signaling
  • genetic alterations
  • molecular targeted therapy
  • precision medicine

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Published Papers (16 papers)

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Research

Jump to: Review

13 pages, 1279 KiB  
Article
Selective Role of TNFα and IL10 in Regulation of Barrier Properties of the Colon in DMH-Induced Tumor and Healthy Rats
by Viktoria Bekusova, Tatiana Zudova, Ilyas Fatyykhov, Arina Fedorova, Salah Amasheh and Alexander G. Markov
Int. J. Mol. Sci. 2022, 23(24), 15610; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415610 - 09 Dec 2022
Viewed by 1057
Abstract
Recently it has been reported that the tumor adjacent colon tissues of 1,2-dymethylhydrazine induced (DMH)-rats revealed a high paracellular permeability. We hypothesized that the changes might be induced by cytokines. Colorectal cancer is accompanied by an increase in tumor necrosis factor alpha (TNFα) [...] Read more.
Recently it has been reported that the tumor adjacent colon tissues of 1,2-dymethylhydrazine induced (DMH)-rats revealed a high paracellular permeability. We hypothesized that the changes might be induced by cytokines. Colorectal cancer is accompanied by an increase in tumor necrosis factor alpha (TNFα) and interleukin 10 (IL10) that exert opposite regulatory effects on barrier properties of the colon, which is characterized by morphological and functional segmental heterogeneity. The aim of this study was to analyze the level of TNFα and IL10 in the colon segments of DMH-rats and to investigate their effects on barrier properties of the proximal and distal parts of the colon in healthy rats. Enzyme immunoassay analysis showed decreased TNFα in tumors in the distal part of the colon and increased IL10 in proximal tumors and in non-tumor tissues. Four-hour intraluminal exposure of the colon of healthy rats with cytokines showed reduced colon barrier function dependent on the cytokine: TNFα decreased it mainly in the distal part of the colon, whereas IL10 decreased it only in the proximal part. Western blot analysis revealed a more pronounced influence of IL10 on tight junction (TJ) proteins expression by down-regulation of the TJ proteins claudin-1, -2 and -4, and up-regulation of occludin only in the proximal part of the colon. These data may indicate a selective role of the cytokines in regulation of the barrier properties of the colon and a prominent role of IL10 in carcinogenesis in its proximal part. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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22 pages, 3864 KiB  
Article
A Transcriptome and Methylome Study Comparing Tissues of Early and Late Onset Colorectal Carcinoma
by Muhammad G Kibriya, Maruf Raza, Anthony Quinn, Mohammed Kamal, Habibul Ahsan and Farzana Jasmine
Int. J. Mol. Sci. 2022, 23(22), 14261; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214261 - 17 Nov 2022
Cited by 4 | Viewed by 1422
Abstract
There is an increase in the incidence of early onset colorectal carcinoma (EOCRC). To better understand if there is any difference in molecular pathogenesis of EOCRC and late onset colorectal carcinoma (LOCRC), we compared the clinical, histological, transcriptome, and methylome profile of paired [...] Read more.
There is an increase in the incidence of early onset colorectal carcinoma (EOCRC). To better understand if there is any difference in molecular pathogenesis of EOCRC and late onset colorectal carcinoma (LOCRC), we compared the clinical, histological, transcriptome, and methylome profile of paired CRC and healthy colonic tissue from 67 EOCRC and 98 LOCRC patients. The frequency of stage 3 CRC, lymph node involvement, lymphovascular invasion, and perineural invasion was higher in the EOCRC group. Many of the cancer related pathways were differentially expressed in CRC tissue in both EOCRC and LOCRC patients. However, the magnitude of differential expression for some groups of genes, such as DNA damage repair genes and replication stress genes, were significantly less pronounced in the EOCRC group, suggesting less efficient DNA damage repair to be associated with EOCRC. A more marked methylation of “growth factor receptor” genes in LOCRC correlated with a more pronounced down-regulation of those genes in that group. From a therapeutic point of view, more over-expression of fatty acid synthase (FASN) among the LOCRC patients may suggest a better response of FASN targeted therapy in that group. The age of onset of CRC did not appear to modify the response of cis-platin or certain immune checkpoint inhibitors. We found some differences in the molecular pathogenesis in EOCRC and LOCRC that may have some biological and therapeutic significance. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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16 pages, 2136 KiB  
Article
Targeted Sequencing of Cytokine-Induced PI3K-Related Genes in Ulcerative Colitis, Colorectal Cancer and Colitis-Associated Cancer
by Nurul Nadirah Razali, Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Azyani Yahaya and Norfilza M. Mokhtar
Int. J. Mol. Sci. 2022, 23(19), 11472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911472 - 29 Sep 2022
Cited by 2 | Viewed by 1556
Abstract
Chronic relapsing inflammatory bowel disease is strongly linked to an increased risk of colitis-associated cancer (CAC). One of the well-known inflammatory carcinogenesis pathways, phosphatidylinositol 3-kinase (PI3K), was identified to be a crucial mechanism in long-standing ulcerative colitis (UC). The goal of this study [...] Read more.
Chronic relapsing inflammatory bowel disease is strongly linked to an increased risk of colitis-associated cancer (CAC). One of the well-known inflammatory carcinogenesis pathways, phosphatidylinositol 3-kinase (PI3K), was identified to be a crucial mechanism in long-standing ulcerative colitis (UC). The goal of this study was to identify somatic variants in the cytokine-induced PI3K-related genes in UC, colorectal cancer (CRC) and CAC. Thirty biopsies (n = 8 long-standing UC, n = 11 CRC, n = 8 paired normal colorectal mucosa and n = 3 CAC) were subjected to targeted sequencing on 13 PI3K-related genes using Illumina sequencing and the SureSelectXT Target Enrichment System. The Genome Analysis Toolkit was used to analyze variants, while ANNOVAR was employed to detect annotations. There were 5116 intronic, 355 exonic, 172 untranslated region (UTR) and 59 noncoding intronic variations detected across all samples. Apart from a very small number of frameshifts, the distribution of missense and synonymous variants was almost equal. We discovered changed levels of IL23R, IL12Rß1, IL12Rß2, TYK2, JAK2 and OSMR in more than 50% of the samples. The IL23R variant in the UTR region, rs10889677, was identified to be a possible variant that might potentially connect CAC with UC and CRC. Additional secondary structure prediction using RNAfold revealed that mutant structures were more unstable than wildtype structures. Further functional research on the potential variants is, therefore, highly recommended since it may provide insight on the relationship between inflammation and cancer risk in the cytokine-induced PI3K pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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19 pages, 2972 KiB  
Article
S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway
by Luigi Borzacchiello, Roberta Veglia Tranchese, Roberta Grillo, Roberta Arpino, Laura Mosca, Giovanna Cacciapuoti and Marina Porcelli
Int. J. Mol. Sci. 2022, 23(14), 7673; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147673 - 12 Jul 2022
Cited by 4 | Viewed by 1915
Abstract
Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between [...] Read more.
Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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21 pages, 4648 KiB  
Article
Tissue-Specific Downregulation of Fatty Acid Synthase Suppresses Intestinal Adenoma Formation via Coordinated Reprograming of Transcriptome and Metabolism in the Mouse Model of Apc-Driven Colorectal Cancer
by James Drury, Lyndsay E. A. Young, Timothy L. Scott, Courtney O. Kelson, Daheng He, Jinpeng Liu, Yuanyan Wu, Chi Wang, Heidi L. Weiss, Teresa Fan, Matthew S. Gentry, Ramon Sun and Yekaterina Y. Zaytseva
Int. J. Mol. Sci. 2022, 23(12), 6510; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126510 - 10 Jun 2022
Cited by 9 | Viewed by 2459
Abstract
Altered lipid metabolism is a potential target for therapeutic intervention in cancer. Overexpression of Fatty Acid Synthase (FASN) correlates with poor prognosis in colorectal cancer (CRC). While multiple studies show that upregulation of lipogenesis is critically important for CRC progression, the contribution of [...] Read more.
Altered lipid metabolism is a potential target for therapeutic intervention in cancer. Overexpression of Fatty Acid Synthase (FASN) correlates with poor prognosis in colorectal cancer (CRC). While multiple studies show that upregulation of lipogenesis is critically important for CRC progression, the contribution of FASN to CRC initiation is poorly understood. We utilize a C57BL/6-Apc/Villin-Cre mouse model with knockout of FASN in intestinal epithelial cells to show that the heterozygous deletion of FASN increases mouse survival and decreases the number of intestinal adenomas. Using RNA-Seq and gene set enrichment analysis, we demonstrate that a decrease in FASN expression is associated with inhibition of pathways involved in cellular proliferation, energy production, and CRC progression. Metabolic and reverse phase protein array analyses demonstrate consistent changes in alteration of metabolic pathways involved in both anabolism and energy production. Downregulation of FASN expression reduces the levels of metabolites within glycolysis and tricarboxylic acid cycle with the most significant reduction in the level of citrate, a master metabolite, which enhances ATP production and fuels anabolic pathways. In summary, we demonstrate the critical importance of FASN during CRC initiation. These findings suggest that targeting FASN is a potential therapeutic approach for early stages of CRC or as a preventive strategy for this disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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10 pages, 1191 KiB  
Communication
Effect of Hypoxia-Induced Micro-RNAs Expression on Oncogenesis
by Giorgia Moriondo, Giulia Scioscia, Piera Soccio, Pasquale Tondo, Cosimo Carlo De Pace, Roberto Sabato, Maria Pia Foschino Barbaro and Donato Lacedonia
Int. J. Mol. Sci. 2022, 23(11), 6294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116294 - 04 Jun 2022
Cited by 9 | Viewed by 1967
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the [...] Read more.
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. An aberrant regulation of gene expression by miRNAs is associated with numerous diseases, including cancer. MiRNAs expression can be influenced by various stimuli, among which hypoxia; however, the effects of different types of continuous hypoxia (moderate or marked) on miRNAs are still poorly studied. Lately, some hypoxia-inducible miRNAs (HRMs, hypoxia-regulated miRNAs) have been identified. These HRMs are often activated in different types of cancers, suggesting their role in tumorigenesis. The aim of this study was to evaluate changes in miRNAs expression both in moderate continuous hypoxia and marked continuous hypoxia to better understand the possible relationship between hypoxia, miRNAs, and colorectal cancer. We used RT-PCR to detect the miRNAs expression in colorectal cancer cell lines in conditions of moderate and marked continuous hypoxia. The expression of miRNAs was analyzed using a two-way ANOVA test to compare the differential expression of miRNAs among groups. The levels of almost all analyzed miRNAs (miR-21, miR-23b, miR-26a, miR-27b, and miR-145) were greater in moderate hypoxia versus marked hypoxia, except for miR-23b and miR-21. This study identified a series of miRNAs involved in the response to different types of continuous hypoxia (moderate and marked), highlighting that they play a role in the development of cancer. To date, there are no other studies that demonstrate how these two types of continuous hypoxia could be able to activate different molecular pathways that lead to a different expression of specific miRNAs involved in tumorigenesis. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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14 pages, 2647 KiB  
Article
Captopril, a Renin–Angiotensin System Inhibitor, Attenuates Tumour Progression in the Regenerating Liver Following Partial Hepatectomy
by Georgina E. Riddiough, Katrina A. Walsh, Theodora Fifis, Georgios Kastrappis, Bang M. Tran, Elizabeth Vincan, Vijayaragavan Muralidharan, Christopher Christophi, Claire L. Gordon and Marcos V. Perini
Int. J. Mol. Sci. 2022, 23(9), 5281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095281 - 09 May 2022
Cited by 4 | Viewed by 2370
Abstract
(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin–angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver [...] Read more.
(1) Liver regeneration following partial hepatectomy for colorectal liver metastasis (CRLM) has been linked to tumour recurrence. Inhibition of the renin–angiotensin system (RASi) attenuates CRLM growth in the non-regenerating liver. This study investigates whether RASi exerts an antitumour effect within the regenerating liver following partial hepatectomy for CRLM and examines RASi-induced changes in the tumour immune microenvironment; (2) CRLM in mice was induced via intrasplenic injection of mouse colorectal tumour cells, followed by splenectomy on Day 0. Mice were treated with RASi captopril (250 mg/kg/day), or saline (control) from Day 4 to Day 16 (endpoint) and underwent 70% partial hepatectomy on Day 7. Liver and tumour samples were characterised by flow cytometry and immunofluorescence; (3) captopril treatment reduced tumour burden in mice following partial hepatectomy (p < 0.01). Captopril treatment reduced populations of myeloid-derived suppressor cells (MDSCs) (CD11b+Ly6CHi p < 0.05, CD11b+Ly6CLo p < 0.01) and increased PD-1 expression on infiltrating hepatic tissue-resident memory (TRM)-like CD8+ (p < 0.001) and double-negative (CD4-CD8-; p < 0.001) T cells; (4) RASi reduced CRLM growth in the regenerating liver and altered immune cell composition by reducing populations of immunosuppressive MDSCs and boosting populations of PD-1+ hepatic TRMs. Thus, RASi should be explored as an adjunct therapy for patients undergoing partial hepatectomy for CRLM. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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11 pages, 1958 KiB  
Article
Lost by Transcription: Fork Failures, Elevated Expression, and Clinical Consequences Related to Deletions in Metastatic Colorectal Cancer
by Marcel Smid, Saskia M. Wilting and John W. M. Martens
Int. J. Mol. Sci. 2022, 23(9), 5080; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095080 - 03 May 2022
Cited by 2 | Viewed by 1345
Abstract
Among the structural variants observed in metastatic colorectal cancer (mCRC), deletions (DELs) show a size preference of ~10 kb–1 Mb and are often found in common fragile sites (CFSs). To gain more insight into the biology behind the occurrence of these specific DELs [...] Read more.
Among the structural variants observed in metastatic colorectal cancer (mCRC), deletions (DELs) show a size preference of ~10 kb–1 Mb and are often found in common fragile sites (CFSs). To gain more insight into the biology behind the occurrence of these specific DELs in mCRC, and their possible association with outcome, we here studied them in detail in metastatic lesions of 429 CRC patients using available whole-genome sequencing and corresponding RNA-seq data. Breakpoints of DELs within CFSs are significantly more often located between two consecutive replication origins compared to DELs outside CFSs. DELs are more frequently located at the midpoint of genes inside CFSs with duplications (DUPs) at the flanks of the genes. The median expression of genes inside CFSs was significantly higher than those of similarly-sized genes outside CFSs. Patients with high numbers of these specific DELs showed a shorter progression-free survival time on platinum-containing therapy. Taken together, we propose that the observed DEL/DUP patterns in expressed genes located in CFSs are consistent with a model of transcription-dependent double-fork failure, and, importantly, that the ability to overcome the resulting stalled replication forks decreases sensitivity to platinum-containing treatment, known to induce stalled replication forks as well. Therefore, we propose that our DEL score can be used as predictive biomarker for decreased sensitivity to platinum-containing treatment, which, upon validation, may augment future therapeutic choices. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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16 pages, 2859 KiB  
Article
HOXB9 Overexpression Promotes Colorectal Cancer Progression and Is Associated with Worse Survival in Liver Resection Patients for Colorectal Liver Metastases
by Eirini Martinou, Carla Moller-Levet, Dimitrios Karamanis, Izhar Bagwan and Angeliki M. Angelidi
Int. J. Mol. Sci. 2022, 23(4), 2281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042281 - 18 Feb 2022
Cited by 8 | Viewed by 2345
Abstract
As is known, HOXB9 is an important factor affecting disease progression and overall survival (OS) in cancer. However, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the role of HOXB9 in CRC progression and its association with OS in [...] Read more.
As is known, HOXB9 is an important factor affecting disease progression and overall survival (OS) in cancer. However, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the role of HOXB9 in CRC progression and its association with OS in colorectal liver metastases (CRLM). We analysed differential HOXB9 expression in CRC using the Tissue Cancer Genome Atlas database (TCGA). We modulated HOXB9 expression in vitro to assess its impact on cell proliferation and epithelial-mesenchymal transition (EMT). Lastly, we explored the association of HOXB9 protein expression with OS, using an institutional patient cohort (n = 110) who underwent liver resection for CRLM. Furthermore, HOXB9 was upregulated in TCGA-CRC (n = 644) vs. normal tissue (n = 51) and its expression levels were elevated in KRAS mutations (p < 0.0001). In vitro, HOXB9 overexpression increased cell proliferation (p < 0.001) and upregulated the mRNA expression of EMT markers (VIM, CDH2, ZEB1, ZEB2, SNAI1 and SNAI2) while downregulated CDH1, (p < 0.05 for all comparisons). Conversely, HOXB9 silencing disrupted cell growth (p < 0.0001). High HOXB9 expression (HR = 3.82, 95% CI: 1.59–9.2, p = 0.003) was independently associated with worse OS in CRLM-HOXB9-expressing patients after liver resection. In conclusion, HOXB9 may be associated with worse OS in CRLM and may promote CRC progression, whereas HOXB9 silencing may inhibit CRC growth. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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15 pages, 1724 KiB  
Article
MicroRNA-199b Deregulation Shows Oncogenic Properties and Promising Clinical Value as Circulating Marker in Locally Advanced Rectal Cancer Patients
by Andrea Santos, Ion Cristóbal, Jaime Rubio, Cristina Caramés, Melani Luque, Marta Sanz-Alvarez, Miriam Morales-Gallego, Juan Madoz-Gúrpide, Federico Rojo and Jesús García-Foncillas
Int. J. Mol. Sci. 2022, 23(4), 2203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042203 - 17 Feb 2022
Cited by 3 | Viewed by 1714
Abstract
The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response [...] Read more.
The identification of robust prognostic markers still represents a need in locally advanced rectal cancer (LARC). MicroRNAs (miRs) have progressively emerged as promising circulating markers, overcoming some limitations that traditional biopsy comprises. Tissue miR-199b deregulation has been reported to predict outcome and response to neoadjuvant chemoradiotherapy (nCRT) in LARC, and was also found to be associated with disease progression in colorectal cancer. However, its biological and clinical relevance remains to be fully clarified. Thus, we observed here that miR-199b regulates cell migration, aggressiveness, and cell growth, and inhibits colonosphere formation and induces caspase-dependent apoptosis. Moreover, miR-199b expression was quantified by real-time PCR in plasma samples from LARC patients and its downregulation was observed in 22.7% of cases. This alteration was found to be associated with higher tumor size (p = 0.002) and pathological stage (p = 0.020) after nCRT. Notably, we observed substantially lower global miR-199b expression associated with patient downstaging (p = 0.009), as well as in non-responders compared to those cases who responded to nCRT in both pre- (p = 0.003) and post-treatment samples (p = 0.038). In concordance, we found that miR-199b served as a predictor marker of response to neoadjuvant therapy in our cohort (p = 0.011). Altogether, our findings here demonstrate the functional relevance of miR-199b in this disease and its potential value as a novel circulating marker in LARC. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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Review

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19 pages, 1660 KiB  
Review
Relationship between Epithelial-to-Mesenchymal Transition and Tumor-Associated Macrophages in Colorectal Liver Metastases
by Aurora Gazzillo, Michela Anna Polidoro, Cristiana Soldani, Barbara Franceschini, Ana Lleo and Matteo Donadon
Int. J. Mol. Sci. 2022, 23(24), 16197; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416197 - 19 Dec 2022
Cited by 11 | Viewed by 2716
Abstract
The liver is the most common metastatic site in colorectal cancer (CRC) patients. Indeed, 25–30% of the cases develop colorectal liver metastasis (CLM), showing an extremely poor 5-year survival rate and resistance to conventional anticancer therapies. Tumor-associated macrophages (TAMs) provide a nurturing microenvironment [...] Read more.
The liver is the most common metastatic site in colorectal cancer (CRC) patients. Indeed, 25–30% of the cases develop colorectal liver metastasis (CLM), showing an extremely poor 5-year survival rate and resistance to conventional anticancer therapies. Tumor-associated macrophages (TAMs) provide a nurturing microenvironment for CRC metastasis, promoting epithelial-to-mesenchymal transition (EMT) through the TGF-β signaling pathway, thus driving tumor cells to acquire mesenchymal properties that allow them to migrate from the primary tumor and invade the new metastatic site. EMT is known to contribute to the disruption of blood vessel integrity and the generation of circulating tumor cells (CTCs), thus being closely related to high metastatic potential in numerous solid cancers. Despite the fact that it is well-recognized that the crosstalk between tumor cells and the inflammatory microenvironment is crucial in the EMT process, the association between the EMT and the role of TAMs is still poorly understood. In this review, we elaborated on the role that TAMs exert in the induction of EMT during CLM development. Since TAMs are the major source of TGF-β in the liver, we also focused on novel insights into their role in TGF-β-induced EMT. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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28 pages, 1160 KiB  
Review
TGF-β Signaling in Metastatic Colorectal Cancer (mCRC): From Underlying Mechanism to Potential Applications in Clinical Development
by Xiaoshuang Li, Yanmin Wu and Tian Tian
Int. J. Mol. Sci. 2022, 23(22), 14436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214436 - 20 Nov 2022
Cited by 14 | Viewed by 2971
Abstract
Colorectal cancer (CRC) is a serious public health issue, and it has the leading incidence and mortality among malignant tumors worldwide. CRC patients with metastasis in the liver, lung or other distant sites always have poor prognosis. Thus, there is an urgent need [...] Read more.
Colorectal cancer (CRC) is a serious public health issue, and it has the leading incidence and mortality among malignant tumors worldwide. CRC patients with metastasis in the liver, lung or other distant sites always have poor prognosis. Thus, there is an urgent need to discover the underlying mechanisms of metastatic colorectal cancer (mCRC) and to develop optimal therapy for mCRC. Transforming growth factor-β (TGF-β) signaling plays a significant role in various physiologic and pathologic processes, and aberrant TGF-β signal transduction contributes to mCRC progression. In this review, we summarize the alterations of the TGF-β signaling pathway in mCRC patients, the functional mechanisms of TGF-β signaling, its promotion of epithelial–mesenchymal transition, its facilitation of angiogenesis, its suppression of anti-tumor activity of immune cells in the microenvironment and its contribution to stemness of CRC cells. We also discuss the possible applications of TGF-β signaling in mCRC diagnosis, prognosis and targeted therapies in clinical trials. Hopefully, these research advances in TGF-β signaling in mCRC will improve the development of new strategies that can be combined with molecular targeted therapy, immunotherapy and traditional therapies to achieve better efficacy and benefit mCRC patients in the near future. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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12 pages, 1127 KiB  
Review
Deciphering Mechanisms of Action of Sortilin/Neurotensin Receptor-3 in the Proliferation Regulation of Colorectal and Other Cancers
by Jean Mazella
Int. J. Mol. Sci. 2022, 23(19), 11888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911888 - 06 Oct 2022
Cited by 3 | Viewed by 2018
Abstract
The purpose of this review is to decipher the mechanisms of the pathways leading to the complex roles of neurotensin (NTS) receptor-3, also called sortilin, and of its soluble counterpart (sSortilin/NTSR3) in a large amount of physiological and pathological functions, particularly in cancer [...] Read more.
The purpose of this review is to decipher the mechanisms of the pathways leading to the complex roles of neurotensin (NTS) receptor-3, also called sortilin, and of its soluble counterpart (sSortilin/NTSR3) in a large amount of physiological and pathological functions, particularly in cancer progression and metastasis. Sortilin/NTSR3 belongs to the family of type I transmembrane proteins that can be shed to release its extracellular domain from all the cells expressing the protein. Since its discovery, extensive investigations into the role of both forms of Sortilin/NTSR3 (membrane-bound and soluble form) have demonstrated their involvement in many pathophysiological processes from cancer development to cardiovascular diseases, Alzheimer’s disease, diabetes, and major depression. This review focuses particularly on the implication of membrane-bound and soluble Sortilin/NTSR3 in colorectal cancer tissues and cells depending on its ability to be associated either to neurotrophins (NTs) or to NTS receptors, as well as to other cellular components such as integrins. At the end of the review, some hypotheses are suggested to counteract the deleterious effects of these proteins in order to develop effective anti-cancer treatments. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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16 pages, 1767 KiB  
Review
MicroRNA Methylome Signature and Their Functional Roles in Colorectal Cancer Diagnosis, Prognosis, and Chemoresistance
by Rashidah Baharudin, Nurul Qistina Rus Bakarurraini, Imilia Ismail, Learn-Han Lee and Nurul Syakima Ab Mutalib
Int. J. Mol. Sci. 2022, 23(13), 7281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137281 - 30 Jun 2022
Cited by 6 | Viewed by 2343
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite significant advances in the diagnostic services and patient care, several gaps remain to be addressed, from early detection, to identifying prognostic variables, effective treatment for the metastatic disease, and [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite significant advances in the diagnostic services and patient care, several gaps remain to be addressed, from early detection, to identifying prognostic variables, effective treatment for the metastatic disease, and the implementation of tailored treatment strategies. MicroRNAs, the short non-coding RNA species, are deregulated in CRC and play a significant role in the occurrence and progression. Nevertheless, microRNA research has historically been based on expression levels to determine its biological significance. The exact mechanism underpinning microRNA deregulation in cancer has yet to be elucidated, but several studies have demonstrated that epigenetic mechanisms play important roles in the regulation of microRNA expression, particularly DNA methylation. However, the methylation profiles of microRNAs remain unknown in CRC patients. Methylation is the next major paradigm shift in cancer detection since large-scale epigenetic alterations are potentially better in identifying and classifying cancers at an earlier stage than somatic mutations. This review aims to provide insight into the current state of understanding of microRNA methylation in CRC. The new knowledge from this study can be utilized for personalized health diagnostics, disease prediction, and monitoring of treatment. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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20 pages, 453 KiB  
Review
Proteomic Profiling and Biomarker Discovery in Colorectal Liver Metastases
by Geoffrey Yuet Mun Wong, Connie Diakos, Thomas J. Hugh and Mark P. Molloy
Int. J. Mol. Sci. 2022, 23(11), 6091; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116091 - 29 May 2022
Cited by 7 | Viewed by 2850
Abstract
Colorectal liver metastases (CRLM) are the leading cause of death among patients with metastatic colorectal cancer (CRC). As part of multimodal therapy, liver resection is the mainstay of curative-intent treatment for select patients with CRLM. However, effective treatment of CRLM remains challenging as [...] Read more.
Colorectal liver metastases (CRLM) are the leading cause of death among patients with metastatic colorectal cancer (CRC). As part of multimodal therapy, liver resection is the mainstay of curative-intent treatment for select patients with CRLM. However, effective treatment of CRLM remains challenging as recurrence occurs in most patients after liver resection. Proposed clinicopathologic factors for predicting recurrence are inconsistent and lose prognostic significance over time. The rapid development of next-generation sequencing technologies and decreasing DNA sequencing costs have accelerated the genomic profiling of various cancers. The characterisation of genomic alterations in CRC has significantly improved our understanding of its carcinogenesis. However, the functional context at the protein level has not been established for most of this genomic information. Furthermore, genomic alterations do not always result in predicted changes in the corresponding proteins and cancer phenotype, while post-transcriptional and post-translational regulation may alter synthesised protein levels, affecting phenotypes. More recent advancements in mass spectrometry-based technology enable accurate protein quantitation and comprehensive proteomic profiling of cancers. Several studies have explored proteomic biomarkers for predicting CRLM after oncologic resection of primary CRC and recurrence after curative-intent resection of CRLM. The current review aims to rationalise the proteomic complexity of CRC and explore the potential applications of proteomic biomarkers in CRLM. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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27 pages, 1167 KiB  
Review
MicroRNAs and ‘Sponging’ Competitive Endogenous RNAs Dysregulated in Colorectal Cancer: Potential as Noninvasive Biomarkers and Therapeutic Targets
by Brian G. Jorgensen and Seungil Ro
Int. J. Mol. Sci. 2022, 23(4), 2166; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042166 - 16 Feb 2022
Cited by 11 | Viewed by 3286
Abstract
The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells [...] Read more.
The gastrointestinal (GI) tract in mammals is comprised of dozens of cell types with varied functions, structures, and histological locations that respond in a myriad of ways to epigenetic and genetic factors, environmental cues, diet, and microbiota. The homeostatic functioning of these cells contained within this complex organ system has been shown to be highly regulated by the effect of microRNAs (miRNA). Multiple efforts have uncovered that these miRNAs are often tightly influential in either the suppression or overexpression of inflammatory, apoptotic, and differentiation-related genes and proteins in a variety of cell types in colorectal cancer (CRC). The early detection of CRC and other GI cancers can be difficult, attributable to the invasive nature of prophylactic colonoscopies. Additionally, the levels of miRNAs associated with CRC in biofluids can be contradictory and, therefore, must be considered in the context of other inhibiting competitive endogenous RNAs (ceRNA) such as lncRNAs and circRNAs. There is now a high demand for disease treatments and noninvasive screenings such as testing for bloodborne or fecal miRNAs and their inhibitors/targets. The breadth of this review encompasses current literature on well-established CRC-related miRNAs and the possibilities for their use as biomarkers in the diagnoses of this potentially fatal GI cancer. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer)
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