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A Definitive Role of RhoC in Metastasis of Orthotopic Lung Cancer in Mice

¹ Department of Cardiology, Respiratory and Nephrology, Regeneration and Advanced Medical Science, Graduate School of Medicine, Gifu University, and Departments of ² Gene Therapy and Regenerative Medicine and ³ Gastroenterology and Hematology, Pathophysiology and Regulatory Medical Sciences, Gifu University School of Medicine, Gifu and ⁴ Division of Gene Therapy and Regenerative Medicine, Cognitive and Molecular Research Institute of Brain Diseases, Kurume University, and ⁵ Department of Pediatrics, Kurume University School of Medicine, Kurume; and ⁶ Department of Food Science, Kyoto Women’s University, Kyoto, Japan

Purpose: Lung cancer is a major cause of cancer death, and its incidence is increasing in the world. Conventional therapies remain less effective for metastases of lung cancer, leading to poor prognosis of this disorder. The present study investigates pathological roles of RhoC in metastasis of lung cancer using a clinically relevant mouse model of lung cancer.

Experimental Design: RhoA, RhoC, dominant-negative Rho (dnRho) or green fluorescent protein gene was retrovirally transduced to murine lung cancer cells. For in vivo study, these transduced cells were intrapulmonary inoculated in syngeneic mice, and subsequently, growth and metastasis were analyzed. Migration and invasion activities were further investigated by in vitro chemotaxic chamber assays. Expression levels and activities of certain matrix metalloproteinases (MMPs) were explored by reverse transcription-PCR and gelatin zymography.

Results: Metastasis of lung cancer in the animal model, as well as in vitro migration and invasion, were significantly enhanced or inhibited by overexpression of RhoC or dnRho, respectively, without affecting the growth of primary tumors. Expression levels of certain MMPs and the activity of MMP-2 were significantly enhanced or suppressed by overexpression of RhoC or dnRho, respectively.

Conclusion: RhoC plays a crucial role in metastasis of lung cancer. RhoC does not affect tumor growth but enhances the metastatic nature of lung cancer by not only stimulating cell motility but also up-regulating certain MMPs. Attenuation of RhoC activity may be a potential target in the development of a novel strategy for treating metastasis of lung cancer.

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