研究者詳細 - 藤原　智洋

論文 - 藤原　智洋

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A rare manifestation of extraskeletal myxoid chondrosarcoma with a huge expanding hematoma.

Toshinori Omori, Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Aki Yoshida, Hiroyuki Yanai, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 24 ( 2 ) 377 - 381 2019年3月

Mini-open excision of osteoid osteoma using intraoperative O-arm/Stealth navigation.

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Eiji Nakata, Yusuke Mochizuki, Masahiro Kiyono, Aki Yoshida, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 24 ( 2 ) 337 - 341 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Although osteoid osteomas have traditionally been treated by surgical excision, radiofrequency ablation (RFA) has gained favor as a less invasive procedure. However, RFA is contraindicated for osteoid osteomas close to the skin or crucial neurovascular structures, and is not covered by national health insurance in Japan. The aim of the present study was to evaluate the efficacy of surgical excision of osteoid osteomas using intraoperative navigation. METHODS: We performed a retrospective review of five patients with osteoid osteoma who underwent a mini-open excision using O-arm/Stealth navigation at our institution. The osteoid osteomas were excised using a cannulated cutter or curetted out with the assistance of navigation. RESULTS: Complete excision was achieved in all patients, which was confirmed by pathological examination. The mean skin incision was 2.1 cm (range, 1.5 to 3.0 cm) and the mean duration required for setup three-dimensional image was 15 min (range, 12 to 20 min). Although the mean visual analog scale score was 7 (range, 4 to 8) before surgery, all patients experienced relief from their characteristic pain immediately after surgery, with the mean scores of 2.2 (range, 1 to 3) and 0 at 2 days and 4 weeks after surgery, respectively. There was no intra-operative complication related to the navigation and no recurrence was observed during the mean follow-up period of 25 months (range, 13 to 33 months). CONCLUSIONS: Mini-open excision using intraoperative O-arm/Stealth navigation is a safe and accurate procedure for patients with osteoid osteoma, which could cover the limitation of RFA.

DOI： 10.1016/j.jos.2018.09.017

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Identification of Circulating Exosomal Marker in Synovial Sarcoma

Suguru Yokoo, Tomohiro Fujiwara, Aki Yoshida, Masahiro Kiyono, Yusuke Mochizuki, Koji Demiya, Joe Hasei, Toshiyuki Kunisada, Yusuke Yoshioka, Koji Ueda, Takahiro Ochiya, Toshifumi Ozaki

CANCER SCIENCE 109 570 - 570 2018年12月

Intraoperative O-arm-navigated resection in musculoskeletal tumors.

Tomohiro Fujiwara, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Eiji Nakata, Ryuichi Nakahara, Aki Yoshida, Toshifumi Ozaki

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 23 ( 6 ) 1045 - 1050 2018年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Although emerging evidence has suggested that computer-assisted navigation allows surgeons to plan the optimal level of resection without compromising the surgical margins, the precise accuracy of the procedures has been unclear. The aim of this study was to investigate the accuracy and safety of the musculoskeletal tumor resection using O-arm/Stealth intraoperative navigation assistance. METHODS: A retrospective study of six patients with bone and soft tissue tumors who underwent surgical resection using O-arm/Stealth navigation system was performed. The histological diagnosis was osteosarcoma, metastatic bone tumor, leiomyosarcoma, undifferentiated sarcoma, and synovial sarcoma, respectively. Tumor resection was performed according to planned osteotomy planes determined on O-arm/Stealth three-dimensional intraoperative images. The resection accuracy, length of time for the procedures, surgical margins, and perioperative complications were evaluated. RESULTS: The distances between the entry and exit points for the planned and actual cuts were 1.5 ± 0.3 mm and 2.3 ± 0.3 mm, respectively, and the mean discrepancy of the osteotomy angle was 2.8 ± 1.2°. The mean length of time required for navigation was 14 min. A histological examination revealed clear margins in all patients. There were no complications related to navigation, and no patients developed local recurrence during a mean follow-up of 30.6 months. CONCLUSIONS: The O-arm/Stealth intraoperative CT navigation system provides safe and accurate osteotomy in musculoskeletal tumor resections. However, surgeons should keep in mind and be careful of minimal errors during osteotomy, which are around 2 mm from the planned line.

DOI： 10.1016/j.jos.2018.06.012

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Autopsy Case of a Penetrating Wound to the Left Cerebral Hemisphere Caused by an Accidental Shooting With a Crossbow. 国際誌

Takeshi Kondo, Motonori Takahashi, Azumi Kuse, Mai Morichika, Kanako Nakagawa, Yoshihiro Tagawa, Tomoya Taniguchi, Yuji Taguchi, Tomohiro Fujiwara, Junpei Tsuchiya, Masahiko Nakamura, Makoto Sakurada, Migiwa Asano, Yasuhiro Ueno

The American journal of forensic medicine and pathology 39 ( 2 ) 164 - 168 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

A crossbow is a bow that shoots an arrow when a gun-like trigger is pulled. Deaths caused by accidental crossbow shootings are extremely rare. Here we describe an autopsy case of a penetrating wound to the left cerebral hemisphere caused by an accidental shooting with a crossbow. A man in his early 60s who lived with his wife and had used crossbows for 20 years as his hobby was found one early morning in the shed of his house, collapsed and bleeding from the head and neck. He was taken to a hospital and died after approximately 3 days of conservative treatment. At autopsy, a penetrating wound between the upper part of the left anterior neck and the left frontoparietal region was evident. Traumatic intracerebral hematoma was observed in the left frontal lobe, and severe traumatic subarachnoid hemorrhage was present throughout the brain. Cerebral contusion and hematoma without any organization were noted around the penetration. The cause of death was determined to be cerebral contusion and intracerebral hematoma due to the penetrating wound by the crossbow arrow. He was probably trying to load an arrow into the crossbow by placing it on the floor, pointing upward, and made a mistake in its operation that resulted in the shooting of the arrow. This case is unique because it was a rare accidental death caused by a crossbow arrow, and a detailed histopathological examination was performed.

DOI： 10.1097/PAF.0000000000000381

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Clinical and Functional Significance of Intracellular and Extracellular microRNA-25-3p in Osteosarcoma.

Aki Yoshida, Tomohiro Fujiwara, Koji Uotani, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Eiji Nakata, Toshiyuki Kunisada, Toshifumi Ozaki

Acta medica Okayama 72 ( 2 ) 165 - 174 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although there is considerable evidence indicating that the dysregulation of microRNAs (miRNAs) in malignant tumors plays a role in tumor development, the overall function of miRNAs and their clinicopathological significance are not well understood. In this retrospective analysis of 45 biopsy specimens from osteosarcoma (OS) patients, we investigated the functional and clinical significance of miR-25-3p in OS, which we previously identified as a highly expressed miRNA in OS patients' serum. We observed that miR-25-3p dysregulation in human OS tissues was negatively correlated with the clinical prognosis, whereas the expression level of its target gene, Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), was positively correlated with the clinical prognosis. Endogenous miR-25-3p upregulation promoted tumor growth, invasion, and drug resistance, which was consistent with DKK3 silencing in OS cells. In addition, secretory miR-25-3p was embedded in tumor-derived exosomes, where it promoted capillary formation and the invasion of vascular endothelial cells. Overall, our results show that miR-25-3p has intracellular and extracellular oncogenic functions as well as clinicopathological relevance in OS, indicating its potential as a novel diagnostic and therapeutic tool for the clinical management of this disease.

DOI： 10.18926/AMO/55857

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【運動器画像診療の最前線】部位別・疾患別画像診療の最前線骨腫瘍の画像診療

中田英二, 国定俊之, 長谷井嬢, 藤原智洋, 尾崎敏文

関節外科 37 ( 4月増刊 ) 130 - 143 2018年4月

記述言語：日本語出版者・発行元：(株)メジカルビュー社

＜画像診療のポイント＞●骨腫瘍の診療において、画像検査は鑑別診断や治療効果判定だけではなく、手術にも有用である。●鑑別診断について、初診医は一般整形外科医であることが多く、悪性を疑う所見を見逃さないことが重要である。●骨腫瘍にはそれぞれ特徴的な年齢分布や好発部位があり、年齢や既往歴などの臨床情報も踏まえ、複数の画像検査の情報を組み合わせて診断を行う。●単純X線像の読影では、腫瘍の局在と性状に注目する。●CTは、単純X線検査では評価が困難な部位の診断、微細な石灰化や骨化の有無の検出などを調べるのに適している。また、三次元的に骨病変を評価することができ、術前計画にも有用である。さらに、近年はコンピュータ支援手術により術中に短時間で高画質の2D・3D画像が取得でき、画像データをナビゲーションシステムに送信することで、より低侵襲かつ安全で確実な手術が可能となっている。●MRIは優れたコントラスト分解能をもち、腫瘍の進展や質的診断、治療効果判定などに有用である。●PET/CTは、良悪性の鑑別診断、病期診断、治療効果判定に有用である。●各画像検査には長所と短所があるため、その特徴を理解しておくことが重要である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00282&link_issn=&doc_id=20180406150013&doc_link_id=10.18885%2FJ00282.2018192551&url=https%3A%2F%2Fdoi.org%2F10.18885%2FJ00282.2018192551&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Liquid biopsy using tumor-derived exosomes for Ewing sarcoma patients

Aki Yoshida, Tomohiro Fujiwara, Koji Uotani, Shintaro Iwata, Yusuke Yoshioka, Koji Ueda, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Joe Hasei, Toshiyuki Kunisada, Takahiro Ochiya, Toshifumi Ozaki

CANCER SCIENCE 109 312 - 312 2018年1月

Circulating MicroRNA-92b-3p as a Novel Biomarker for Monitoring of Synovial Sarcoma. 国際誌

Koji Uotani, Tomohiro Fujiwara, Aki Yoshida, Shintaro Iwata, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Toshiyuki Kunisada, Ken Takeda, Joe Hasei, Kunihiko Numoto, Yutaka Nezu, Tsukasa Yonemoto, Takeshi Ishii, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki

Scientific reports 7 ( 1 ) 14634 - 14634 2017年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The lack of useful biomarkers is a crucial problem for patients with soft tissue sarcomas (STSs). Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel impact as biomarkers for patients with malignant diseases, but their significance in synovial sarcoma (SS) patients remains unknown. Initial global miRNA screening using SS patient serum and SS cell culture media identified a signature of four upregulated miRNAs. Among these candidates, miR-92b-3p secretion from SS cells was confirmed, which was embedded within tumour-derived exosomes rather than argonaute-2. Animal experiments revealed a close correlation between serum miR-92b-3p levels and tumour dynamics. Clinical relevance was validated in two independent clinical cohorts, and we subsequently identified that serum miR-92b-3p levels were significantly higher in SS patients in comparison to that in healthy individuals. Moreover, serum miR-92b-3p was robust in discriminating patients with SS from the other STS patients and reflected tumour burden in SS patients. Overall, liquid biopsy using serum miR-92b-3p expression levels may represent a novel approach for monitoring tumour dynamics of SS.

DOI： 10.1038/s41598-017-12660-5

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Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction. 国際誌

Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Cancer science 108 ( 9 ) 1870 - 1880 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.

DOI： 10.1111/cas.13316

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Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma. 国際誌

Tomohiro Fujiwara, Koji Uotani, Aki Yoshida, Takuya Morita, Yutaka Nezu, Eisuke Kobayashi, Akihiko Yoshida, Takenori Uehara, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Ken Takeda, Toshiyuki Kunisada, Machiko Kawamura, Akira Kawai, Takahiro Ochiya, Toshifumi Ozaki

Oncotarget 8 ( 20 ) 33375 - 33392 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. METHODS: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. RESULTS: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. CONCLUSIONS: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

DOI： 10.18632/oncotarget.16498

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Atypical manifestation of lung metastasis 17 years after initial diagnosis of low-grade central osteosarcoma.

Tomohiro Fujiwara, Mai Oda, Akihiko Yoshida, Koichi Ogura, Hirokazu Chuman, Masahiko Kusumoto, Akira Kawai

Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 22 ( 2 ) 357 - 361 2017年3月

悪性骨盤腫瘍一時的創外固定を利用した早期リハビリテーション

国定俊之, 武田健, 藤原智洋, 野田知之, 尾崎敏文, 堅山佳美, 千田益生

日本創外固定・骨延長学会雑誌 28 147 - 147 2017年2月

腫瘍型人工関節置換術とそのリハビリテーション

国定俊之, 藤原智洋, 長谷井嬢, 堅山佳美, 千田益生, 尾﨑敏文

The Japanese journal of rehabilitation medicine = リハビリテーション医学 54 ( 3 ) 209 - 213 2017年

記述言語：日本語出版者・発行元：公益社団法人日本リハビリテーション医学会

<p>腫瘍型人工関節置換術は，術後のリハビリテーションを早期に開始することができるため，社会復帰が早いという利点がある．しかし，筋肉などの軟部組織の再建が症例ごとに異なっているため，変形性関節症などに対して行われる一般的な人工関節置換術とは異なるアプローチが必要である．腫瘍切除により，多くの筋肉が起始・停止部で切離されるため，これらの筋肉をできるだけ解剖学的位置に再建することが機能回復において重要となる．金属の人工関節と筋肉は生物学的な癒合が期待できないが，ポリプロピレンメッシュを使用することで，強固な固定力が獲得できる．本稿では，近位・遠位大腿骨，近位脛骨の腫瘍型人工関節のリハビリテーションについて解説する．</p>

DOI： 10.2490/jjrmc.54.209

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その他リンク： http://search.jamas.or.jp/link/ui/2017296069

miR-135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma 査読

Y. Nezu, K. Hagiwara, Y. Yamamoto, T. Fujiwara, K. Matsuo, A. Yoshida, A. Kawai, T. Saito, T. Ochiya

ONCOGENE 35 ( 48 ) 6177 - 6188 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.

DOI： 10.1038/onc.2016.157

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網羅的解析による滑膜肉腫由来circulating cell-free microRNAの特定および検証

魚谷弘二, 藤原智洋, 吉田晶, 森田卓也, 大森敏規, 上原健敬, 杉生和久, 小松原将, 武田健, 国定俊之, 根津悠, 岩田慎太郎, 川井章, 落谷孝広, 尾崎敏文

日本整形外科学会雑誌 90 ( 8 ) S1560 - S1560 2016年8月

Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas. 国際誌

Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Scientific reports 6 28953 - 28953 2016年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

DOI： 10.1038/srep28953

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創外固定を利用した悪性骨盤腫瘍に対する早期リハビリテーション

国定俊之, 藤原智洋, 野田知之, 堅山佳美, 千田益生, 尾崎敏文

The Japanese Journal of Rehabilitation Medicine ( JARM2016 ) I438 - I438 2016年6月

手・足部発生の類骨骨腫の治療経験

小松原将, 武田健, 森田卓也, 杉生和久, 魚谷弘二, 大森敏規, 上原健敬, 吉田晶, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 90 ( 6 ) S1396 - S1396 2016年6月

PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma. 国際誌

Mio Hirahata, Mitsuhiko Osaki, Yusuke Kanda, Yui Sugimoto, Yusuke Yoshioka, Nobuyoshi Kosaka, Fumitaka Takeshita, Tomohiro Fujiwara, Akira Kawai, Hisao Ito, Takahiro Ochiya, Futoshi Okada

Cancer medicine 5 ( 5 ) 892 - 902 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P < 0.05). These results indicated that PAI-1, a target gene of miR-143, regulates invasion and lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.

DOI： 10.1002/cam4.651

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