Abstract
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.
Highlights
Skeletal muscles represent the largest tissue mass of the body and can be distinguished from smooth muscles as they are composed of striated myofibers of multinucleated syncytia, coming from the fusion of myocytes
1A, uals subjected to electrostimulation exercise, as compared to T0 plasma as control, showed miR-133a showed an upregulation in most the probands analysed, if with difa differential expression of miR-1 and miR-133a
The classical physiological function of tropomyosins has been defined by considering their role in muscle contraction [64]
Summary
Skeletal muscles represent the largest tissue mass of the body and can be distinguished from smooth muscles as they are composed of striated myofibers of multinucleated syncytia, coming from the fusion of myocytes. Actin filaments are cross-linked by α-actinin, interacting with myosin to form actomyosin bundles, the actin stress fibres These are fundamental for cell adhesion to the extracellular matrix (ECM), and in tumour cells a depletion of these fibres stimulate cell migration [7]. TPM4 is able to promote cell migration modulating F-actin assembly in lung cancer [8], high levels of TPM4 have been detected in HCC patients with distant metastasis. The overexpression of this tropomyosin seems to enhance cell migration and viability by negative SUSD2 regulation [9]
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