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

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.

Potential diagnostic role of circulating MiRNAs in colorectal cancer

“…31 The results obtained from the current study showed that miR-133a is downregulated in CRC and that it has perfect significance when related to tumor staging, grading and lymph node metastasis with sensitivity 98.6% and specificity 88% suggesting its role as important biomarker for diagnosis and prognosis of CRC consistent with Wan et al, 2014 and Caporali et al, 2021. 32,33 In the current study, miR-133a expression was considerably decreased in the serum of CRC patients with late stage and low grade, consistent with earlier reports by Luo et al, 2013, 34 which also contradicts many studies, indicating that miR-133a is not simply an oncogene as many papers reported. 31 MiR-574-3p has been verified as a tumor suppressor in several cancers such as prostate cancer, bladder cancer, gastric cancer, ovarian cancer and chronic myeloid leukemia.…”

“… 31 The results obtained from the current study showed that miR-133a is downregulated in CRC and that it has perfect significance when related to tumor staging, grading and lymph node metastasis with sensitivity 98.6% and specificity 88% suggesting its role as important biomarker for diagnosis and prognosis of CRC consistent with Wan et al, 2014 and Caporali et al, 2021. 32 , 33 …”

Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer

“…Abnormal activation of the Hedgehog signaling pathway can lead to the occurrence and progression of colorectal cancer (Guo et al, 2022). The enhancement of mitotic spindle and myogenesis pathways indicated that cell division, microfilament cytoskeleton, and stress fibers formation process were active (Caporali et al, 2021). The downregulation of pancreas beta cells, oxidative phosphorylation, peroxisome, and mTORC1 signaling showed the disturbance of nutrient metabolism of samples in the high-risk subgroup.…”

Response of circulating miRNAs to acute exercise: A systematic Review and Meta-Analysis

“…The genes that produce miR-133a and miR-1 are clustered together, with the two miRNAs transcribed as a single primary transcript (44). In skeletal muscle, miR-133a stimulates muscle growth by reducing myoblast differentiation, possibly through downregulation of tropomyosin-4, an actin binding component of the cytoskeleton (45). In cardiac tissue, miR-133a is linked to hypertrophy, although so far only as a marker of disease (e.g.…”