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Published on: January 7, 2010
Nonmuscle myosin IIA and IIB differentially modulate migration and alter gene expression in primary mouse tumorigenic
Debdatta Halder1, Shekhar Saha1,2, Raman K Singh1,3
1School of Biological Sciences, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India.
Abstract:
Though many cancers are known to show up-regulation of nonmuscle myosin (NM) IIA and IIB, the mechanism by which NMIIs aid in cancer development remains unexplored. Here we demonstrate that tumor-generating, fibroblast-like cells isolated from 3-methylcholanthrene (3MC)-induced murine tumor exhibit distinct phospho-dependent localization of NMIIA and NMIIB at the perinuclear area and tip of the filopodia and affect cell migration differentially. While NMIIA-KD affects protrusion dynamics and increases cell directionality, NMIIB-KD lowers migration speed and increases filopodial branching. Strategically located NMIIs at the perinuclear area colocalize with the linker of nucleoskeleton and cytoskeleton (LINC) protein Nesprin2 and maintain the integrity of the nuclear-actin cap. Interestingly, knockdown of NMIIs results in altered expression of genes involved in epithelial-to-mesenchymal transition, angiogenesis, and cellular senescence. NMIIB-KD cells display down-regulation of Gsc and Serpinb2, which is strikingly similar to Nesprin2-KD cells as assessed by quantitative PCR analysis. Further gene network analysis predicts that NMIIA and NMIIB may act on similar pathways but through different regulators. Concomitantly, knockdown of NMIIA or NMIIB lowers the growth rate and tumor volume of 3MC-induced tumor in vivo. Altogether, these results open a new window to further investigate the effect of LINC-associated perinuclear actomyosin complex on mechanoresponsive gene expression in the growing tumor.
Insights
Nonmuscle myosin (NM) IIA and IIB are crucial for cancer development, influencing cell migration and tumor growth. Targeting these myosins offers a new therapeutic strategy for cancer treatment.
Area of Science:
- Cell Biology
- Cancer Research
- Biophysics
Background:
- Nonmuscle myosin (NM) IIA and IIB are upregulated in many cancers, but their precise roles in tumorigenesis are unclear.
- Understanding the mechanisms of NMII involvement is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the role of nonmuscle myosin IIA (NMIIA) and IIB in cancer development and cell migration.
- To explore the interaction of NMIIs with the linker of nucleoskeleton and cytoskeleton (LINC) complex and their impact on nuclear-actin cap integrity.
- To assess the effect of NMII knockdown on gene expression related to cancer progression and tumor growth in vivo.
Main Methods:
- Isolation of tumor-generating fibroblast-like cells from 3-methylcholanthrene (3MC)-induced murine tumors.
- Knockdown studies (NMIIA-KD, NMIIB-KD) to analyze effects on cell migration, filopodial dynamics, and protrusion.
- Immunofluorescence microscopy to study localization of NMIIs, Nesprin2, and the nuclear-actin cap.
- Quantitative PCR and gene network analysis to assess gene expression changes.
- In vivo tumor growth assays following NMII knockdown.
Main Results:
- NMIIA and NMIIB exhibit distinct phospho-dependent localization in tumor cells, affecting migration differently (NMIIA-KD: increased directionality; NMIIB-KD: decreased speed, increased branching).
- Perinuclear NMIIs colocalize with Nesprin2, maintaining nuclear-actin cap integrity.
- NMII knockdown alters expression of genes involved in epithelial-to-mesenchymal transition, angiogenesis, and senescence.
- NMIIB-KD shows downregulation of Gsc and Serpinb2, similar to Nesprin2-KD.
- Knockdown of NMIIA or NMIIB significantly reduces tumor growth rate and volume in vivo.
Conclusions:
- Nonmuscle myosins IIA and IIB play critical roles in cancer cell migration, nuclear integrity, and tumor progression.
- The interaction between NMIIs, the LINC complex, and the nuclear-actin cap influences mechanoresponsive gene expression in tumors.
- Targeting NMIIs presents a promising therapeutic strategy for reducing tumor growth and metastasis.
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