ROCK2/ras^Ha co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated...

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Rho-associated coiled-coil containing kinase 2 (ROCK2) plays a role in cell motility and tissue rigidity.
• Ras homologue (RasHa) activation is a known driver of skin carcinogenesis.
• Understanding the interplay between ROCK2, RasHa, and tumor suppressors is crucial for cancer research.

Purpose of the Study:

• To investigate the role of ROCK2 activation in skin carcinogenesis initiated by RasHa.
• To elucidate the molecular mechanisms by which ROCK2 contributes to tumor progression and malignancy.
• To identify potential therapeutic targets by understanding the signaling pathways involved.

Main Methods:

• Utilized genetically engineered mouse models expressing inducible ROCK2 (K14.ROCKer) and epidermal-activated RasHa (HK1.ras1205).
• Administered 4-hydroxytamoxifen (4HT) to activate ROCK2 and observed tumor development over 8 and 12 weeks.
• Analyzed histopathology, proliferation markers, p53, NF-κB, p21, tenascin C, and p-Mypt1 expression in tumor tissues.

Main Results:

• ROCK2 activation in RasHa-initiated papillomas led to well-differentiated squamous cell carcinoma (wdSCC) with p53 loss and increased NF-κB.
• Tumor progression to SCC required p21 loss, and was associated with increased tenascin C and tissue rigidity.
• Cessation of ROCK2 activation induced p21-associated differentiation, while sustained activation in later SCCs drove invasion via p21 loss and increased contractility.

Conclusions:

• ROCK2 activation is a critical driver of malignancy in RasHa-initiated and promoted skin tumors, particularly in the context of p53 loss and NF-κB activation.
• Increased tissue rigidity and altered cell contractility mediated by ROCK2 are key factors in tumor progression and invasion.
• A novel antagonism between p21 and RasHa/ROCK2/NF-κB signaling was identified, highlighting p21's role in inhibiting early-stage malignant progression.