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27. Chondromodulin-1 directly suppresses growth of human cancer cells

Author

Kondo Naoki, Yamagiwa Hiroshi, Kitahara Hiroshi, Hayami Tadashi, Ali Md, Ishibashi Osamu, Yoshizawa Tatsuya, Kawashima Hiroyuki, Mera Hisashi, Ogose Akira, and Endo Naoto

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Chondromodulin-1 (ChM1), an endogenous anti-angiogenic factor expressed in cartilage, has been suggested to inhibit invasion of endothelial cells into cartilage. In addition, the ectopic administration of ChM1 has been reported to suppress tumorigenesis in vivo. However, it is unclear whether the anti-tumor effect is due to not only the anti-vascularization effect of ChM1, but also its direct action against oncocytes. In the present study, we sought to determine whether ChM1 has a direct action on tumor cells. Methods BrdU incorporation assay was performed on human umbilical vein endothelial cells (HUVECs), normal human dermal fibroblasts (NHDFs), HepG2 cells and HeLa cells in the presence or absence of recombinant human ChM1 (rhChM1). An adenovirus that expresses ChM1, Ad-ChM1, was established and applied to the tumor xenografted in vivo, and to in vitro tumor cells cultured on plates or in soft agar. Cell cycle-related proteins and the phosphorylation of Erk, Akt, and GSK3β, the downstream molecules of the extracellular matrix-integrin signaling pathways, in HepG2 cells treated with or without Ad-ChM1 were detected by western blot analysis. Luciferase reporter assays of STAT, GAS, and ISRE, which participate in another cytokine signaling pathway, ware performed in HepG2, HeLa, and HUVEC cells. Results ChM1 suppressed BrdU incorporation in HUVECs and in HepG2 cells dose-dependently, but did not suppress BrdU incorporation in NHDFs and HeLa cells cultured on plates. In soft agar, however, ChM1 suppressed the growth of HeLa cells, as well as HepG2 cells. Western blot analyses demonstrated that ChM1 decreased the levels of cyclin D1, cyclin D3, and cdk6 and increased those of p21cip1 without affecting the phosphorylation levels of Erk, Akt, and GSK3β in HepG2 cells. The luciferase reporter assay demonstrated that ChM1 suppressed the transcriptional activities of STAT and GAS but not of ISRE. Conclusion ChM1 directly suppressed the proliferation of tumor cells in an anchorage-independent manner. However, ChM1 did not alter the phosphorylation of downstream molecules, at which the signaling pathways through growth factor and cytokine receptors converge with the anchorage-dependent pathway. Our results show that ChM1 has a direct anti-tumor effect; moreover, this effect occurs by inhibiting the STAT signaling pathway.

Published
2009
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28. Pycnodysostosis with a Cathepsin K Mutation : A Case Report

Author

YAMAGIWA, Hiroshi, ASAOKA, Mayumi, KATO, Hisayoshi, SHIBATA, Minoru, and ENDO, Naoto

Subjects
nonunion, Pycnodysostosis, mutation, cathepsin K, histomorphometric analysis
Abstract

Pycnodysostosis (PKND) is a type of osteosclerosing bone disease. Recent studies have demonstrated that several cathepsin K mutations can be identified in PKND families. A fifty-three-year-old Japanese woman diagnosed with PKND with typical features suffered from the nonunion of the right tibial shaft. We did open reduction and performed a vascularized fibular graft using an external fixator. A low-intensity pulsed ultrasound device was used three months after surgery. Union of the tibia was completed about one year after surgery. Histomorphometric analysis of the iliac bone revealed that the patient had low turnover bone with increased bone volume. Analysis of the cathepsin K coding region from the genomic DNA of the patient and her family (consanguineous parents and three sisters who were all of normal stature) revealed that the patient had a deletion of genomic DNA nucleotide 426 T in exon 5. Her parents and two sisters had a heterozygous mutation, while one sister had a normal sequence. In summary, a mutation in the cathepsin K gene was identified, providing further evidence that a deficiency in the activity of this enzyme causes PKND.

Published
2001

29. Abstracts of selected papers presented at the 28th Annual Meeting of the Japanese Society of Gastroenterology Kanazawa, Japan, October 1–3, 1986

Author

Ogura, Yoshifumi, Yamagiwa, Hiroshi, Tsuzuki, Toshiharu, Ogata, Yoshiro, Konishi, Ichiro, Nagakawa, Takukazu, Miyazaki, Itsuo, Todoroki, Takeshi, Iwasaki, Yoji, Tanaka, Junichi, Koyama, Kenji, Nakamura, Hiroshi, Nagamori, Seishi, Homma, Sadamu, Kameda, Haruo, Karasawa, E., Saotome, N., Sugiura, N., Miki, M., Kuniyasu, Y., Suyama, Masafumi, Ariyama, Joe, Koga, Michiaki, Yano, Michitami, Tanaka, N., Watanabe, Toshiaki, Ichida, Fumihiro, Yamada, Gotaro, Gibo, Yukio, Saito, Shinobu, Hisamitsu, Toju, Tameda, Yukihiko, Kikkawa, N., Yagyuu, T., Kikkawa, Nobuteru, Sakata, Yuh, Munakata, Akihiro, Fujita, Masahide, Taguchi, Tetsuo, Takahashi, Yutaka, Mai, Masayoshi, Yamaguchi, Toshiharu, Takahashi, Toshio, Noguchi, T., Hamano, K., Eguchi, Hideo, Sugahara, Katsuhiko, Kimura, Kouzaburo, Sarashina, Hiromi, Todoroki, Takeshi, Tanaka, Sachiko, Kitamura, Tsugio, Saito, Akiko, Obata, Hiroshi, Yoshida, Takanobu, Yoshino, Masahiro, Matsui, Osamu, Takashima, Tsutomu, Tokuyama, Katsuyuki, Jinno, Kenji, Kondo, Fukuo, Ebara, Masaaki, Sugihara, Shigetaka, Kojiro, Masamichi, Shoji, Masamitsu, Kobori, Ohichiro, Haruma, Ken, Tokutomi, Tadashi, Saito, T., Kobayashi, M., Shirohzu, Genzan, Kakegawa, Teruo, Yamaki, Goro, Maruyama, Toshihide, Sugihara, Takashi, Mitomi, Toshio, Yamada, Akiyoshi, Itoh, Tadahiko, Yoshida, Tomoharu, Udagawa, Harushi, Tsurumaru, Masahiko, Yasui, Akihiro, Nimura, Yuji, Ri, Sigen, Nabeya, Kin-Ichi, Fujita, Hideharu, Noto, Hirofumi, Sano, Fumio, Uchino, Junichi, Kawaura, Yukimitsu, Mori, Yoshihiro, Kano, Tomoyuki, Ito, Yoshiaki, Hishikawa, Yoshio, Miura, Takashi, Karaki, Yoshiaki, Fujimaki, Masao, Kashiwagi, Toni, Koizumi, Takeo, Hata, Yoshinobu, Itoh, Kazuo, Sato, Shizou, Mimura, Hisashi, Kuniyasu, Yoshio, Takada, Tadanori, Nakajima, Michiko, Itoh, Susumu, Bando, Tsuyoshi, Tanaka, Michio, Aibe, Tsuyoshi, Fujimura, Hiroshi, Hayashi, Yoshiki, Kimoto, Eizo, Ohishi, Hajime, Morita, Tomofumi, Sugano, Shigeo, Abei, Tohru, Ikari, T., Ariyama, J., Ibuki, Yoshikazu, Kuronuma, Yukio, Kodama, Takahiro, Numa, Yoshinori, Saito, K., Kasukawa, R., Kagawa, Hiroyuki, Nishioka, Mikio, Imai, Haruhiko, Kiyosawa, Kendo, Abe, Hirohiko, Tanikawa, Kyuichi, Furusawa, Akihiko, Takase, Kojiro, Kosaka, Yoshitane, Higuchi, Kiyohiro, Matsui, Shinjiro, Watanabe, Satoshi, Ichida, Fumihiro, Kato, Yasuhiro, Shimizu, Masanori, Yuh, Kouichi, Yagisawa, Hitoshi, Komatsu, Masafumi, Maeda, Takashi, Miyazaki, Masako, Ishii, Hideo, Usui, Kou, Oda, M., Komatsu, H., Mizoguchi, Yasuhiro, Kuroki, Tetsuo, Mori, Yoshio, Ogawa, Makoto, Mori, Teruo, Ueda, Shiro, Yoshida, Hiromichi, Wakashin, Yoko, Wakashin, Masafumi, Okuda, Kunio, Watanabe, Yasuyuki, Kawakami, Hiroiku, Nonomura, Akitaka, Ohta, Goroku, Suzuki, Hiroshi, Takino, Tatsuro, Kawaguchi, Hideki, Ichida, Fumihiro, Hinoue, Yoshinobu, Unoura, Masashi, Mizoguchi, Yasuhiro, Kagawa, Hiroyuki, Nishioka, Mikio, Arakawa, Yasuyuki, Amaki, Schuichi, Ikeda, Kenji, Kumada, Hiromitsu, Ikeda, Toshio, Tarao, Kazuo, Nakano, Masami, Saito, Shozo, Takahashi, Akira, Shimamura, Yoshiyuki, Matsuda, Yoshiro, Yasuhara, Minoru, Matsuo, Yutaka, Miyake, Takeo, Matsuo, Y., Watanabe, Akiharu, Nei, Jinichi, Matsuda, Yoshiro, Iwasaki, Ariyoshi, Sugimura, Fumiaki, Yamagata, Susumu, Arakawa, Tetsuo, Kobayashi, Kenzo, Miyamoto, Shintaro, Yukawa, Eiyo, Kitajima, Masaki, Seki, Manabu, Murakami, M., Kobayashi, Y., Mizuno, M., Yoo, J. K., Saita, H., Inoue, R., Inada, M., Miyake, T., Hirai, Nobuyuki, Tanaka, Nobuyoshi, Miyake, Takeo, Ando, Keijiro, Sanuki, Kazutoshi, Inui, Kazuo, Nakazawa, Saburo, Tanaka, Ryoji, Ukida, Minoru, Miyashita, Tadashi, Tobe, Takayoshi, Kosen, Kenzo, Takahashi, Hiroshi, Kadota, Toshio, Tamakuma, Shouetsu, Kitano, Seigo, Sugimachi, Keizo, Nakao, Akimasa, Takagi, Hiroshi, Sawai, Kiyoshi, Takahashi, Toshio, Kusano, Toshiomi, Furukawa, Masato, Yamane, Tetsuro, Takahashi, Toshio, and Iida, Shuhei

Published
1987
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33. Proceedings of the 27th Annual Meeting Matsuyama, Japan, November 7–9, 1985

Author

Rogler, C. E., Muto, Yoshihiro, Uchimura, Masayuki, Kijima, Hiroshi, Watanabe, Hidenobu, Kakita, A., Kambayashi, M., Takahashi, T., Saji, Y., Tsuburaya, T., Uchino, J., Ogura, Yoshifumi, Yamagiwa, Hiroshi, Takehara, Y., Yamashita, K., Shimaguchi, Seikoh, Ariyama, Joe, Tomatsu, Sei, Oi, Itaru, Fuji, Tadasu, Noguchi, Takayoshi, Yamao, Kenji, Nakazawa, Saburo, Suzuki, H., Mizumoto, R., Kumon, Masamitu, Ogata, Takuro, Yamamoto, Kenichi, Sasaki, Kenichi, Kida, Hideo, Nimura, Yuji, Hayakawa, Naokazu, Kamiya, Junichi, Shionoya, Shigehiko, Hata, Yoshinobu, Uchino, Jun-Ichi, Yamane, Takaaki, Mori, Katsutaka, Kinoshita, Hiroaki, Inoue, Tadashi, Takayasu, Kenichi, Moriyama, Noriyuki, Makuuchi, Masatoshi, Takasaki, Ken, Tanaka, Seiichi, Shirakawa, K., Misaki, F., Shibue, Tadashi, Tanaka, Keizo, Asaka, Masahiro, Saito, Masao, Yamagata, Susumu, Utiyama, Yasuo, Kobayashi, K., Arakawa, T., Matsueda, Kei, Muraoka, Akira, Umeda, Noritsugu, Mizumachi, Shyuzi, Okita, Kiwamu, Sakaue, Hiroshi, Akamatsu, Kouichi, Aoki, Teruaki, Nagao, Fusahiro, Watanabe, Yozo, Kidokoro, Tsutomu, Nakano, Satoshi, Kumada, Takashi, Kondo, Takaharu, Hayakawa, Tetsuo, Ogawa, Michio, Matsuda, Yasuki, Mori, Takesada, Yasuda, Hideki, Atomi, Yutaka, Ohnishi, Norihito, Kuroda, Akira, Morioka, Yasuhiko, Satake, Katsusuke, Tsuchiya, Ryoichi, Isaji, Shuji, Mizumoto, Ryuji, Yamamoto, Masahiro, Saitoh, Yoichi, Takeda, Kazunori, Taguchi, Susumu, Funatomi, Hitoshi, Hatta, Yoshio, Ono, Mikiko, Itoshima, Tatsuya, Tanaka, Ryoji, Sato, Shunichi, Sugaya, Hitoshi, Futagawa, Shunji, Kobayashi, Kenichi, Kawasaki, Hironaka, Akamatsu, Kouichi, Ohkubo, Hirotada, Kawarada, Yoshifumi, Mizumoto, Ryuji, Hirasawa, Hiroyuki, Odaka, Michio, Isono, Kaichi, Miura, Soichiro, Hamada, Yoshiki, Bamba, Tadao, Chikamochi, Nobuo, Nezu, R., Okada, A., Okuno, Masahiro, Umeyama, Kaoru, Hiwatashi, Nobuo, Nakajima, Kazuyuki, Fuchigami, Tadahiko, Yao, Tsuneyoshi, Matsueda, Kei, Takazoe, Masakazu, Shoda, Ryosuke, Umeda, Noritsugu, Fukushima, T., Kawamoto, M., Mizutani, Kenji, Nakai, Katsuhiko, Aoki, Katsunori, Morioka, Satoru, Baba, Shozo, Sakamoto, Akio, Usui, Sadahito, Fukuda, Yoshihiro, Tamura, Kazutami, Watanabe, Hikaru, Ueno, Takato, Tanikawa, Kyuichi, Oda, Masaya, Morizane, Toshio, Hashimoto, Hiroyuki, Akamatsu, Kouichi, Shimizu, Ichiro, Shima, Kenji, Sasaki, Kohsuke, Okita, Kiwamu, Suzuki, Toshimitsu, Seto, Yoshifumi, Nakashima, Toshiaki, Kiyosawa, Kendo, Imai, Haruhiko, Shimizu, Yukihiro, Sasaki, Hiroshi, Mori, Teruo, Mori, Yoshio, Ogawa, Makoto, Wakashin, Masafumi, Okuda, Kunio, Kawamoto, Chiaki, Ido, Kenichi, Fujise, Kiyotaka, Nagamori, Seishi, Fujikura, Shinichiro, Shimada, Kazuhiko, Yamaguchi, Kazuhito, Fujimura, Yoshinori, Kihara, Tsuyoshi, Kitamura, Hironobu, Fujiyama, Yoshihide, Asakura, Hitoshi, Kobayashi, Kensuke, Nagura, Hiroshi, Koshikawa, Takashi, Murata, Yuji, Kuroe, Kiyoo, Kawanishi, H., Koyama, K., Senda, S., Kiely, J., Harima, Kazuo, Fuji, Tadasu, Furukawa, Masato, Nakata, Toshinori, Kawahara, Hiroyuki, Komi, Nobuhiko, Ishihara, Yukio, Kondo, Satoshi, Nimura, Yuji, Suda, Koichi, Miyano, Takeshi, Inui, Kazuo, Ohnuma, Toshikazu, Hata, Yoshinobu, Uchino, Jun-Ichi, Yamamichi, Noboru, Konishi, Fumio, Morita, Nobuto, Tanikawa, Yutaka, Kitani, Eiichi, Tamura, Toshikazu, Komi, Nobuhiko, Ohta, Tetsuo, Konishi, Kohji, Utsumi, Makoto, Ueda, Noriyuki, Sasaki, Hideto, Ogura, Yoshifumi, Kawamoto, Toshio, Horiuchi, Itaru, Tada, Kouji, Akamatsu, Kouichi, Nakai, Teiko, Yamashita, Katsuko, Ninomiya, Fuyuhiko, Tanikawa, Kyuichi, Naito, Yasuo, Morita, Keiichi, Hachiya, Hitoshi, Takeuchi, Toshihiko, Onuki, Keizo, Ozaki, Toshihiko, Tsuchiya, Y., Nakamura, H., Nagashima, Hideyuki, Matsushiro, Takashi, Nakai, Masahiro, Isaji, Shuji, Takeuchi, K., Watanabe, G., Ito, T., Idezuki, Y., Isogai, Masatoshi, and Hachisuka, Kitao

Published
1986
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35. Proceedings of the 72nd general meeting Niigata, Japan, March 27–29, 1986

Author

Uchida, Katsuyuki, Watanabe, Hidenobu, Inui, K., Nakazawa, S., Suyama, Masafumi, Ariyama, Joe, Kakita, Akira, Kambayashi, Masaaki, Takahashi, Tsuyoshi, Saji, Yutaka, Takahashi, Masatoshi, Tsuburaya, Toshihiko, Uchino, Junichi, Ogura, Yoshifumi, Yamagiwa, Hiroshi, Wada, Yoshiyuki, Nagai, Hideo, Kuroda, Akira, Morioka, Yasuhiko, Yoshikawa, Tatsuya, Hanyu, Fujio, Tsunoda, Tsukasa, Tsuchiya, Ryoichi, Ouchi, Kiyoaki, Sato, Toshio, Kawaguchi, Hidehiro, Yoshida, Keisuke, Ishihara, Yukio, Sugiyama, Masanori, Kimura, Toshinari, Ibayashi, Hiroshi, Isaji, Shuji, Mizumoto, Ryuji, Ogawa, Michio, Mori, Takesada, Koizumi, Masaru, Fukao, Akira, Oguchi, Hisao, Kawa, Shigeyuki, Takemori, Yasuhiro, Sawabu, Norio, Ichihara, Toru, Nakao, Akimasa, Ishii, Hiromasa, Shigeta, Yohsuke, Matsuda, Yoshiro, Yasuhara, Minoru, Omata, Masao, Ito, Yoshimi, Takahashi, Toru, Himori, Masakado, Kamimura, Tomoteru, Ichida, Fumihiro, Koyama, Wataru, Hasumura, Yasushi, Inagaki, Takao, Sawaki, Shunji, Ichinohe, Akira, Itoh, Susumu, Komatsu, Masafumi, Tobori, Fumio, Inoue, Kyoichi, Aoyama, Keiichi, Abe, Hirohiko, Yamauchi, Kazuaki, Ohishi, Saburo, and Saibara, Toshiji

Published
1986
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37. Correlation between posterior tibial slope and sagittal alignment under weight-bearing conditions in osteoarthritic knees.

Author

Mochizuki, Tomoharu, Tanifuji, Osamu, Koga, Yoshio, Sato, Takashi, Kobayashi, Koichi, Watanabe, Satoshi, Fujii, Toshihide, Yamagiwa, Hiroshi, Katsumi, Ryota, Koga, Hiroshi, Omori, Go, and Endo, Naoto

Subjects
OSTEOARTHRITIS diagnosis, WEIGHT-bearing (Orthopedics), ARTHROPLASTY, ANATOMICAL planes, ORTHOPEDIC surgery
Abstract

Introduction: Posterior tibial slope (PTS) and sagittal alignment are important factors in the etiology of knee osteoarthritis and knee surgery. Clinically, sagittal alignment, which indicates flexion contracture of the knee, contributes to knee function in weight-bearing (WB) conditions. PTS and sagittal alignment under WB conditions in varus osteoarthritic knees are presumed to affect each other, but their association remains unclear. In this study, we aimed to clarify the association. Material and methods: In total, 140 osteoarthritic varus knees were investigated. Under WB conditions, a three-dimensional (3D) alignment assessment system was applied via biplanar long-leg X-rays, using 3D-to-2D image registration technique. The evaluation parameters were as follows: 1) 3D mechanical flexion angle (3DMFA) in regards to sagittal alignment, 2) passing point in the WB line (PP), and 3) medial and lateral PTS. Results: The medial and lateral PTS showed a positive correlation with 3DMFA and PP, respectively (medial PTS–3DMFA, p = 0.001; medial PTS–PP, p < 0.0001; lateral PTS–3DMFA, p < 0.0001; lateral PTS–PP, p = 0.002). The flexion contracture group with 3DMFA >5° demonstrated greater PTS than non-flexion contracture group (medial PTS, p = 0.006; lateral PTS, p = 0.006). Conclusions: Both medial and lateral PTS were correlated with sagittal alignment under WB conditions and were larger in the flexion contracture group. This finding can explain the function to take the load articular surface parallel to the ground for holding the balance in WB conditions in the sagittal plane for osteoarthritic knees. Moreover, surgeons may be required to decrease the PTS during knee arthroplasty to restore full extension in knees of patients with fixed flexion contracture. [ABSTRACT FROM AUTHOR]

Published
2018
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38. Association between anteroposterior laxity in mid-range flexion and subjective healing of instability after total knee arthroplasty.

Author

Mochizuki, Tomoharu, Tanifuji, Osamu, Sato, Takashi, Hijikata, Hiroki, Koga, Hiroshi, Watanabe, Satoshi, Higano, Yukimasa, Ariumi, Akihiro, Murayama, Takayuki, Yamagiwa, Hiroshi, and Endo, Naoto

Subjects
JOINT hypermobility, TOTAL knee replacement reoperation, ARTIFICIAL knees, TOTAL knee replacement, HEALING, RANGE of motion of joints, KNEE surgery, KNEE, KNEE diseases, OSTEOARTHRITIS, WOUND healing, DIAGNOSIS
Abstract

Purpose: Flexion instability following total knee arthroplasty (TKA) is a common indication of early revision. The association between the objective anteroposterior (AP) laxity direction in mid-range flexion and the subjective healing of instability remains unclear; thus, this study aimed to clarify this association.Methods: In this study, 110 knees (74 females, 92 knees; 16 males, 18 knees) with medial pivot implants were examined with a median age of 79 (range 60-92) years for a median follow-up duration of 22 (range 6-125) months. AP laxity was measured using a KT-1000 arthrometer. Self-reported knee instability score was used for the subjective healing of instability.Results: Eighty-seven knees did not feel unstable (Group 0), whereas 23 knees felt unstable (Group 1). There was a significant difference in AP displacement [Group 0: median 6 mm; range 2-15 mm and Group 1: median 8 mm; range 4-14; p < 0.0001]. The threshold value of 7 mm was determined using the area under receiver operating characteristic curve of 0.79 [95% confidence interval (CI) 0.69-0.88, p < 0.0001]. In multivariate analysis, AP displacement of ≥7 mm was an independent risk factor for feelings of instability (odds ratio 7.695; 95% CI 2.306-25.674; p = 0.001).Conclusions: AP laxity of ≥7 mm represents a known cause of feelings of instability. By controlling AP laxity in TKAs, without stiffness in the knee, it is possible to prevent feelings of instability. The clinical relevance is that AP laxity of <7 mm is one of the target areas in TKA.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

Published
2017
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40. Chondromodulin-1 directly suppresses growth of human cancer cells.

Author

Mera, Hisashi, Kawashima, Hiroyuki, Yoshizawa, Tatsuya, Ishibashi, Osamu, Ali, Md Moksed, Hayami, Tadashi, Kitahara, Hiroshi, Yamagiwa, Hiroshi, Kondo, Naoki, Ogose, Akira, and Endo, Naoto

Subjects
CARTILAGE, VASCULAR endothelial growth factors, ENDOTHELIUM, CANCER cells, HELA cells, ADENOVIRUSES
Abstract

Background: Chondromodulin-1 (ChM1), an endogenous anti-angiogenic factor expressed in cartilage, has been suggested to inhibit invasion of endothelial cells into cartilage. In addition, the ectopic administration of ChM1 has been reported to suppress tumorigenesis in vivo. However, it is unclear whether the anti-tumor effect is due to not only the anti-vascularization effect of ChM1, but also its direct action against oncocytes. In the present study, we sought to determine whether ChM1 has a direct action on tumor cells. Methods: BrdU incorporation assay was performed on human umbilical vein endothelial cells (HUVECs), normal human dermal fibroblasts (NHDFs), HepG2 cells and HeLa cells in the presence or absence of recombinant human ChM1 (rhChM1). An adenovirus that expresses ChM1, Ad-ChM1, was established and applied to the tumor xenografted in vivo, and to in vitro tumor cells cultured on plates or in soft agar. Cell cycle-related proteins and the phosphorylation of Erk, Akt, and GSK3β, the downstream molecules of the extracellular matrix-integrin signaling pathways, in HepG2 cells treated with or without Ad-ChM1 were detected by western blot analysis. Luciferase reporter assays of STAT, GAS, and ISRE, which participate in another cytokine signaling pathway, ware performed in HepG2, HeLa, and HUVEC cells. Results: ChM1 suppressed BrdU incorporation in HUVECs and in HepG2 cells dose-dependently, but did not suppress BrdU incorporation in NHDFs and HeLa cells cultured on plates. In soft agar, however, ChM1 suppressed the growth of HeLa cells, as well as HepG2 cells. Western blot analyses demonstrated that ChM1 decreased the levels of cyclin D1, cyclin D3, and cdk6 and increased those of p21cip1 without affecting the phosphorylation levels of Erk, Akt, and GSK3β in HepG2 cells. The luciferase reporter assay demonstrated that ChM1 suppressed the transcriptional activities of STAT and GAS but not of ISRE. Conclusion: ChM1 directly suppressed the proliferation of tumor cells in an anchorage-independent manner. However, ChM1 did not alter the phosphorylation of downstream molecules, at which the signaling pathways through growth factor and cytokine receptors converge with the anchorage-dependent pathway. Our results show that ChM1 has a direct anti-tumor effect; moreover, this effect occurs by inhibiting the STAT signaling pathway. [ABSTRACT FROM AUTHOR]

Published
2009
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