The miR-133a, TPM4 and TAp63γ Role in Myocyte Differentiation Microfilament Remodelling and Colon Cancer Progression

MicroRNAs (miRNAs) play an essential role in the regulation of a number of physiological functions. miR-133a and other muscular miRs (myomiRs) play a key role in muscle cell growth and in some type of cancers. Here, we show that miR133a is upregulated in individuals that undertake physical exercise. We used a skeletal muscle differentiation model to dissect miR-133a’s role and to identify new targets, identifying Tropomyosin-4 (TPM4). This protein is expressed during muscle differentiation, but importantly it is an essential component of microfilament cytoskeleton and stress fibres formation. The microfilament scaffold remodelling is an essential step in cell transformation and tumour progression. Using the muscle system, we obtained valuable information about the microfilament proteins, and the knowledge on these molecular players can be transferred to the cytoskeleton rearrangement observed in cancer cells. Further investigations showed a role of TPM4 in cancer physiology, specifically, we found that miR-133a downregulation leads to TPM4 upregulation in colon carcinoma (CRC), and this correlates with a lower patient survival. At molecular level, we demonstrated in myocyte differentiation that TPM4 is positively regulated by the TA isoform of the p63 transcription factor. In muscles, miR-133a generates a myogenic stimulus, reducing the differentiation by downregulating TPM4. In this system, miR-133a counteracts the differentiative TAp63 activity. Interestingly, in CRC cell lines and in patient biopsies, miR-133a is able to regulate TPM4 activity, while TAp63 is not active. The downregulation of the miR leads to TPM4 overexpression, this modifies the architecture of the cell cytoskeleton contributing to increase the invasiveness of the tumour and associating with a poor prognosis. These results add data to the interesting question about the link between physical activity, muscle physiology and protection against colorectal cancer. The two phenomena have in common the cytoskeleton remodelling, due to the TPM4 activity, that is involved in stress fibres formation.

Download Full-text

Role of MicroRNAs in Colon Cancer Progression and Metastasis

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200825184924 ◽

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.

Download Full-text

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

Current Cancer Drug Targets ◽

10.2174/1568009620666201223154621 ◽

2020 ◽

Vol 20 ◽

Author(s):

Helen Shiphrah Vethakanraj ◽

Niveditha Chandrasekaran ◽

Ashok Kumar Sekar

Keyword(s):

Cell Fate ◽

Cancer Progression ◽

Potential Role ◽

Tumour Progression ◽

Acid Ceramidase ◽

The Core ◽

The Past ◽

Sphingosine 1 Phosphate ◽

Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

Download Full-text

Crosstalk between cancer and haemostasis

Hämostaseologie ◽

10.5482/ha-1160 ◽

2012 ◽

Vol 32 (02) ◽

pp. 95-104 ◽

Cited By ~ 41

Author(s):

C. Bokemeyer ◽

F. Langer

Keyword(s):

Cancer Progression ◽

Tumour Progression ◽

Modern Concept ◽

Anti Cancer ◽

Haematogenous Metastasis ◽

Triangular Network ◽

Cell Dissemination ◽

Patient Subgroups ◽

Tumour Cell Dissemination

SummaryCancer is characterized by bidirectional interrelations between tumour progression, coagulation activation, and inflammation. Tissue factor (TF), the principal initiator of the coagulation protease cascade, is centrally positioned in this complex triangular network due to its pleiotropic effects in haemostasis, angiogenesis, and haematogenous metastasis. While formation of macroscopic thrombi is the correlate of cancer-associated venous thromboembolism (VTE), a major healthcare burden in clinical haematology and oncology, microvascular thrombosis appears to be critically important to blood-borne tumour cell dissemination. In this regard, expression of TF in malignant tissues as well as shedding of TFbearing microparticles into the circulation are thought to be regulated by defined genetic events relevant to pathological cancer progression, thus directly linking Trousseau’s syndrome to molecular tumourigenesis.Because pharmacological inhibition of the TF pathway in selective tumour types and patient subgroups would be in line with the modern concept of individualized, targeted anti-cancer therapy, this review will focus on the role of TF in tumour biology and cancer-associated VTE.

Download Full-text

Abstract 463: The role of cysteinyl leukotriene receptors and tumour associated macrophages in colon cancer progression

10.1158/1538-7445.am2011-463 ◽

2011 ◽

Author(s):

Yuan Zhang ◽

Wondossen Sime ◽

Anita Sjölander

Keyword(s):

Colon Cancer ◽

Cancer Progression ◽

Cysteinyl Leukotriene ◽

Colon Cancer Progression ◽

Leukotriene Receptors

Download Full-text

Abstract 5033: The role of the epigenetic regulator SATB2 in colon cancer progression

10.1158/1538-7445.sabcs18-5033 ◽

2019 ◽

Author(s):

Donal J. Brennan ◽

Kirsha Naicker ◽

Sudipto Das ◽

Bruce Moran ◽

Rut Klinger ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Progression ◽

Epigenetic Regulator ◽

Colon Cancer Progression

Download Full-text

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.

Download Full-text

The role of NDRG1 in the pathology and potential treatment of human cancers

Journal of Clinical Pathology ◽

10.1136/jclinpath-2013-201692 ◽

2013 ◽

Vol 66 (11) ◽

pp. 911-917 ◽

Cited By ~ 37

Author(s):

Dong-Hun Bae ◽

Patric J Jansson ◽

Michael L Huang ◽

Zaklina Kovacevic ◽

Danuta Kalinowski ◽

...

Keyword(s):

Cancer Progression ◽

Anticancer Agents ◽

Tumour Progression ◽

Antitumour Activity ◽

Primary Tumour ◽

Normal Tissues ◽

Human Cancers ◽

Physiological Processes ◽

Cancer Pathology

N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents.

Download Full-text