A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9

Abstract Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

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The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

10.21203/rs.3.rs-618476/v1 ◽

2021 ◽

Author(s):

Eirini Martinou ◽

Giulia Falgari ◽

Angeliki Angelidi ◽

Guy Simpson ◽

Izhar Bagwan ◽

...

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Systematic Reviews ◽

Poor Prognosis ◽

Tumour Growth ◽

Metastatic Potential ◽

Current Evidence ◽

Hox Proteins ◽

The Impact

Abstract Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

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The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

10.21203/rs.3.rs-618476/v3 ◽

2021 ◽

Author(s):

Eirini Martinou ◽

Giulia Falgari ◽

Angeliki Angelidi ◽

Izhar Bagwan

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Systematic Reviews ◽

Poor Prognosis ◽

Tumour Growth ◽

Metastatic Potential ◽

Current Evidence ◽

Hox Proteins ◽

The Impact

Abstract Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

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The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

10.21203/rs.3.rs-618476/v4 ◽

2021 ◽

Author(s):

Eirini Martinou ◽

Giulia Falgari ◽

Izhar Bagwan ◽

Angeliki Angelidi

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Systematic Reviews ◽

Poor Prognosis ◽

Tumour Growth ◽

Metastatic Potential ◽

Current Evidence ◽

Hox Proteins ◽

The Impact

Abstract Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

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Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽

10.3390/cancers11081058 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1058 ◽

Cited By ~ 10

Author(s):

Gener ◽

Rafael ◽

Seras-Franzoso ◽

Perez ◽

Pindado ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Epithelial To Mesenchymal Transition ◽

Distant Metastases ◽

Metastatic Potential ◽

Phenotypic Change ◽

Primary Tumors ◽

Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

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The Role of SATB1 in Tumour Progression and Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms20174156 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4156 ◽

Cited By ~ 1

Author(s):

Glatzel-Plucińska ◽

Piotrowska ◽

Dzięgiel ◽

Podhorska-Okołów

Keyword(s):

Cancer Progression ◽

Poor Prognosis ◽

Tumour Progression ◽

Prognostic Significance ◽

Distant Metastases ◽

Mesenchymal Transition ◽

Epithelial Cancers ◽

Multistep Process ◽

Satb1 Expression

Carcinogenesis is a long-drawn, multistep process, in which metastatic spread is an unequivocal hallmark of a poor prognosis. The progression and dissemination of epithelial cancers is commonly thought to rely on the epidermal-mesenchymal transition (EMT) process. During EMT, epithelial cells lose their junctions and apical-basal polarity, and they acquire a mesenchymal phenotype with its migratory and invasive capabilities. One of the proteins involved in cancer progression and EMT may be SATB1 (Special AT-Rich Binding Protein 1)—a chromatin organiser and a global transcriptional regulator. SATB1 organizes chromatin into spatial loops, providing a “docking site” necessary for the binding of further transcription factors and chromatin modifying enzymes. SATB1 has the ability to regulate whole sets of genes, even those located on distant chromosomes. SATB1 was found to be overexpressed in numerous malignancies, including lymphomas, breast, colorectal, prostate, liver, bladder and ovarian cancers. In the solid tumours, an elevated SATB1 level was observed to be associated with an aggressive phenotype, presence of lymph node, distant metastases, and a poor prognosis. In this review, we briefly describe the prognostic significance of SATB1 expression in most common human cancers, and analyse its impact on EMT and metastasis.

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Covid-19 In Man: A Very Dangerous Affair.

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666210101123801 ◽

2021 ◽

Vol 21 ◽

Author(s):

Giuseppe Lisco ◽

Vito A. Giagulli ◽

Giovanni De Pergola ◽

Anna De Tullio ◽

Edoardo Guastamacchia ◽

...

Keyword(s):

Poor Prognosis ◽

Metabolic Diseases ◽

Systemic Disease ◽

Public Health Issue ◽

Immune System Dysfunction ◽

Data Support ◽

Systemic Spread ◽

The Impact

Background: The novel pandemic of Coronavirus disease 2019 (COVID-19) has becoming a public health issue since March 2020 considering that more than 30 million people were found to be infected worldwide. Particularly, recent evidences suggested that men may be considered as at higher risk of poor prognosis or death once the infection occurred and concerns surfaced in regard of the risk of a possible testicular injury due to SARS-CoV-2 infection. Results: Several data support the existence of a bivalent role of testosterone (T) in driving poor prognosis in patients with COVID-19. On one hand, this is attributable to the fact that T may facilitate SARS-CoV-2 entry in human cells by means of an enhanced expression of transmembrane serine-protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). At the same time, younger man with normal testicular function compared to women of similar age are prone to develop a blunted immune response against SARS-CoV-2, being exposed to less viral clearance and more viral shedding and systemic spread of the disease. Conversely, low levels of serum T observed in hypogonadal men predispose them to a greater background systemic inflammation, cardiovascular and metabolic diseases, and immune system dysfunction, hence driving harmful consequences once SARS-CoV-2 infection occurred. Finally, SARS-CoV-2, as a systemic disease, may also affect testicles with possible concerns for current and future testicular efficiency. Preliminary data suggested that SARS-CoV-2 genome is not normally found in gonads and gametes, therefore sex transmission could be excluded as a possible way to spread the COVID-19. Conclusion: Most data support a role of T as a bivalent risk factor for poor prognosis (high/normal in younger; lower in elderly) in COVID-19. However, the impact of medical treatment aimed to modify T homeostasis for improving the prognosis of affected patients is unknown in this clinical setting. In addition, testicular damage may be a harmful consequence of the infection even in case it occurred asymptomatically but no long-term evidences are currently available to confirm and quantify this phenomenon. Different authors excluded the presence of SARS-CoV-2 in sperm and oocytes, thus limiting worries about both a potential sexual and gamete-to-embryos transmission of COVID-19. Despite these evidence, long-term and well-designed studies are needed to clarify these issues.

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Up-Regulated MicroRNA-27b Promotes Adipocyte Differentiation via Induction of Acyl-CoA Thioesterase 2 Expression

BioMed Research International ◽

10.1155/2019/2916243 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Yuka Murata ◽

Takashi Yamashiro ◽

Takaomi Kessoku ◽

Israt Jahan ◽

Haruki Usuda ◽

...

Keyword(s):

Liver Disease ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Adipocyte Differentiation ◽

Aberrant Expression ◽

Nonalcoholic Fatty Liver ◽

Important Pathway ◽

The Impact ◽

Intracellular Triglyceride

Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of liver pathologies, from simple steatosis to steatohepatitis. Recent studies have increasingly noted the aberrant expression of microRNAs closely related to NAFLD pathologies. We have previously shown the presence of increased levels of microRNA-27b (miR-27b) in patients with NAFLD. In this study, we investigated the role of miR-27b in NAFLD by examining the impact of up-regulated miR-27b on the differentiation of preadipocytes into mature adipocytes. We found that miR-27b-3p remarkably enhances the adipocyte differentiation of 3T3-L1 cells associated with lipid accumulation and intracellular triglyceride contents. Furthermore, we have demonstrated not only that miR-27b-3p induces acyl-CoA thioesterase 2 (ACOT2) expression in 3T3-L1 cells, but also that the knockdown of ACOT2 suppresses lipid accumulation and adipocyte differentiation in both the presence and absence of miR-27b-3p treatment. Our data strongly suggest that the miR-27b-ACOT2 axis is an important pathway in adipocyte differentiation and may play a role in the pathogenesis of NAFLD.

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Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

Journal of Experimental Medicine ◽

10.1084/jem.20071082 ◽

2007 ◽

Vol 204 (12) ◽

pp. 2935-2948 ◽

Cited By ~ 298

Author(s):

Kevin G. Leong ◽

Kyle Niessen ◽

Iva Kulic ◽

Afshin Raouf ◽

Connie Eaves ◽

...

Keyword(s):

Tumor Growth ◽

Poor Prognosis ◽

Epithelial To Mesenchymal Transition ◽

Breast Tumors ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

Slug Expression ◽

Tumor Growth And Metastasis ◽

Notch Activation ◽

E Cadherin

Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

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The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

International Journal of Molecular Sciences ◽

10.3390/ijms19123711 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3711 ◽

Cited By ~ 22

Author(s):

Ovidiu Balacescu ◽

Daniel Sur ◽

Calin Cainap ◽

Simona Visan ◽

Daniel Cruceriu ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Liver Metastases ◽

Cancer Progression ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Cancer Management ◽

Incidence And Mortality ◽

The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

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