Part of our laboratory’s research foundation has been made possible through generous donations from individuals committed to overcoming cancer, as well as from patients, cancer survivors, and caregivers. We extend our heartfelt gratitude to everyone who has supported our research in the past and to those who continue to support us today. To ensure that the research achievements made possible by your generosity contribute to future advances in cancer diagnosis and treatment, we remain committed to pursuing their practical and clinical application.

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Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis

Heishima et al. J Clin Invest. 2021. 131(17):e139933. doi: 10.1172/JCI139933.

Cancer cells metabolize the nutrients they take up through mitochondria, thereby generating energy and synthesizing cellular building blocks such as DNA and proteins. This highly active metabolism is one of the key mechanisms that supports cancer cell growth and metastasis. In this study, Heishima and colleagues discovered petasin, a new class of mitochondrial metabolism inhibitor, in Japanese butterbur (*Petasites japonicus*), an edible plant native to Japan. In experiments using cultured cells and animal models, petasin inhibited the growth of a wide range of cancer cells and strongly suppressed the formation of metastatic lesions. Under the experimental conditions examined, no apparent systemic toxicity or damage to normal tissues was observed, suggesting that petasin may act selectively on cancer cells. Further investigation of its mechanism of action revealed that petasin inhibits respiratory complex I–mediated NAD/NADH metabolism and exerts anticancer effects by impairing the metabolic function of cancer cells. These findings suggest that petasin may provide a foundation for developing new anticancer drugs and therapeutic strategies that target mitochondrial nutrient metabolism while minimizing adverse effects on normal tissues. [Read the full article]

Targeting microRNA-145-mediated progressive phenotypes of early bladder cancer in a molecularly defined in vivo model

Heishima et al. Mol Ther Nucleic Acids. 2023. 33:960-982. doi: 10.1016/j.omtn.2023.06.009.

Bladder cancer is often detected at a relatively early stage, and long-term survival can be expected when treatment is initiated promptly. However, some bladder cancers are more likely to progress to highly aggressive disease, which can result in a shorter survival period. In this study, we developed an animal model that reproduces the molecular and biological characteristics of early-stage bladder cancers prone to progression and investigated the cellular changes that occur during cancer progression. We found that microRNA-145, a small RNA molecule that regulates gene expression, was reduced in Cyclin D1–positive early lesions with a high risk of progressing to more aggressive disease. This reduction was accompanied by increased expression of c-Myc, a key factor that promotes cancer cell metabolism and proliferation. Furthermore, using the animal model, we demonstrated that restoring the reduced levels of microRNA-145 decreased c-Myc expression and suppressed progression to highly aggressive lesions. [Read the full article]

Prognostic significance of circulating microRNA-214 and -126 in dogs with appendicular osteosarcoma receiving amputation and chemotherapy

Heishima et al. BMC Vet Res. 2019. 15(1):39. doi: 10.1186/s12917-019-1776-1.

Osteosarcoma is a rare cancer that primarily affects children and adolescents. Because the number of patients is limited, conducting research is challenging, and the available diagnostic and treatment options remain limited. In contrast, osteosarcoma is known to occur relatively frequently in certain large dog breeds. In this study, we used naturally occurring osteosarcoma in dogs as a research model and examined two microRNAs found in the blood: microRNA-214 and microRNA-126. Our findings suggest that these microRNAs may serve as biomarkers for predicting survival and the time to metastasis in dogs with osteosarcoma. By comparing the similarities and differences between osteosarcoma in humans and dogs, this research highlights the potential for developing new diagnostic approaches for this rare cancer. [Read the full article]

MicroRNA-214 Promotes Apoptosis in Canine Hemangiosarcoma by Targeting the COP1-p53 Axis

Heishima et al. PLoS One. 2015. 10(9):e0137361. doi: 10.1371/journal.pone.0137361.

Angiosarcoma is a malignant tumor arising from cells that form blood vessels and occurs mainly in older adults. Although it most commonly develops in the skin, particularly on the head, it can also arise in internal organs such as the liver, kidneys, and spleen. This form, known as visceral angiosarcoma, is especially rare. Because many aspects of its development and progression remain poorly understood, there is an urgent need for effective diagnostic and therapeutic approaches. In dogs, visceral hemangiosarcoma occurs relatively frequently in certain large breeds and most commonly develops in the spleen and liver. In this study, we used canine visceral hemangiosarcoma cells to investigate the mechanisms that drive tumor cell proliferation. We found that microRNA-214 levels were reduced in hemangiosarcoma cells. Loss of microRNA-214 led to increased expression of COP1, a protein that suppresses the activity of p53, an important tumor suppressor often referred to as the “guardian of the genome.” This mechanism may enable cancer cells to evade cell death and continue proliferating rapidly. Furthermore, restoring microRNA-214 in hemangiosarcoma cells efficiently induced cancer cell death. These findings suggest that canine hemangiosarcoma may provide valuable insights for developing new treatments for angiosarcoma, a rare cancer in humans. [Read the full article]

Other Publications and Research Achievements (researchmap)

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