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J. Biol. Chem., Vol. 279, Issue 18, 18679-18687, April 30, 2004

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Selective Expression and Functional Characteristics of Three Mammalian Hyaluronan Synthases in Oncogenic Malignant Transformation^*

Naoki Itano¶, Takahiro Sawai, Fukiko Atsumi||, Osamu Miyaishi**, Shun'ichiro Taniguchi, Reiji Kannagi, Michinari Hamaguchi¶¶, and Koji Kimata

From the Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480–1195, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, the ^||Laboratory Animal Research Center and ^**Second Department of Pathology, Aichi Medical University, Nagakute, Aichi 480–1195, the Department of Molecular Oncology and Angiology, Angio-Aging Division, Research Center on Aging and Adaptation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Program of Molecular Pathology, Aichi Cancer Center, Research Institute, Nagoya 464-8681, the ^¶¶Department of Molecular Pathogenesis, Nagoya University School of Medicine, Showa-ku, Nagoya 466, Japan

Malignant transformation of fibroblasts and epithelial cells is often accompanied by increased hyaluronan production and accumulation. Despite recent progress in the study of hyaluronan biosynthesis, the mechanisms underlying the transformation-induced overproduction of hyaluronan have not been elucidated. Here we report that activity and transcriptional levels of hyaluronan synthase (HAS) significantly increased after oncogenic malignant transformation of a rat 3Y1 fibroblast cell line. Of three HAS isoforms (HAS1, HAS2, and HAS3), only HAS2 gene expression was increased in the v-Ha-ras transformed 3Y1 cells, which show less malignancy. In contrast, both HAS1 and HAS2 expressions were elevated in the highly malignant cells transformed with v-src and/or v-fos. To assess the contribution of HAS expression to the oncogenic malignant transformation, we established stable cell transfectants expressing sense and antisense HAS genes. Antisense suppression of the HAS2 expression significantly decreased hyaluronan production in the cells transformed by the oncogenic v-Ha-ras and eventually led to a reduction in tumorigenicity in the rat peritoneum. The introduction of the HAS1 and HAS2 genes promoted the growth of subcutaneous tumors in a manner dependent on the levels of hyaluronan synthesis. Significant growth promotion was observed within a wide range of HAS1 expression. In contrast, the growth stimulation was only seen within a narrow range of HAS2 expression, and high levels of HAS2 expression even inhibited tumor growth. These results suggest that proper regulation of the expression of each HAS isoform is required for optimal malignant transformation and tumor growth.

Received for publication, December 3, 2003 , and in revised form, January 9, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB097568 and AB097569.

^* This study was supported by grants from the Core Research for Evolutional Science and Technology of the Japan Science and Technology Corporation, the preparatory grant for the research at the Division of Matrix Glycoconjugates, Research Center for Infectious Disease, Aichi Medical University, grants-in-aid for Young Scientists (B) and grants-in-aid for Scientific Research on Priority Areas from the Japan's Ministry of Education, Culture, Sports, Science and Technology, the Aichi Cancer Research Foundation, and special research funds from Seikagaku Corporation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-52-264-4811 (ext. 2095); Fax: 81-561-63-3532; E-mail: itano{at}amugw.aichi-med-u.ac.jp.

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