学位論文の要旨
Clinicopathological significance and impact on outcomes of the
gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in
patients with colorectal cancer: Overexpression of the IGFBP-3
gene is a useful predictor of outcomes in patients with colorectal
cancer.
(大腸癌における IGF ファミリー遺伝子発現の臨床的意義)
Naoto Yamamoto
山本直人
Yokohama City University Department of surgery
横浜市立大学 大学院医学研究科 外科治療学
( Doctoral Supervisor: Munetaka Masuda, Professor )
学位論文の要旨
Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is a useful predictor of outcomes in patients with colorectal cancer.
(大腸癌における IGF ファミリー遺伝子発現の臨床的意義)
https://doi.org/10.3892/ol.2017.5936
【背景と目的】大腸癌の発生リスクとして食餌や血中インスリンレベルやインスリン様増殖因子
Insulin-like growth factors (IGFs)の活性の関与が報告されている(Ma et al., 1999, Shikata et al., 2013, Clayton et al., 2011)．IGF ファミリーは，リガンドである IGF-1, IGF-2 やその受容体である IGF-1R およびIGF-2R，調節因子である IGF binding protein type 1-6 (IGFBP1-6)より構成される．IGF， IGF-1R および IGFBP の異常発現は、大腸癌を含むいくつかの悪性腫瘍において同定されている (Durai et al., 2005)．さまざまな癌種において，腫瘍増殖，浸潤，および転移に関与することが報告さ れている．しかしながら，大腸癌組織における各遺伝子発現の臨床的意義の報告は少ない．本研究で は，202 人の大腸癌患者から得られた癌組織および隣接正常粘膜において，IGF-1，IGF-2、IGF-1R およびIGFBP-3 遺伝子の mRNA 発現レベルを測定し、発現レベルが臨床病理学的特徴および大 腸癌患者の臨床転帰と関連するかどうかを検討した． 【対象と方法】2002 年から 2006 年の間に横浜市立大学附属市民総合医療センター消化器病センタ ーおよび神奈川県立がんセンターで大腸癌に対して外科治療を施行した症例で，術前化学療法など の前治療歴のない202 例とした．切除検体から癌組織及び近傍の正常粘膜を採取し，コンパウンドに 包埋して-80℃で保存した． -80℃で保存した大腸癌組織及び近接正常粘膜より mRNA を抽出し，
reverse transcription 反応にて cDNA を作成した．この際には凍結切片のヘマトキシリン-エオジン
染色を行い，マニュアルダイセクションを施行して80%以上の癌細胞が存在するものを癌組織として扱
った．このがん組織及び正常粘膜からのcDNA をテンプレートとして定量 PCR 法にて IGF-1, IGF-2, IGF-1R, IGFBP-3 遺伝子の相対的発現量を測定し，臨床病理学的因子および生存との関係を検討 した．
【結果】大腸癌組織と近接正常粘膜における各遺伝子発現の比較では，IGF-1R 遺伝子発現は癌組
織において有意に高かった(P<0.001)．IGF-1 遺伝子発現は癌組織において有意に低く(P<0.001)， IGF-2 および IGFBP-3 遺伝子では有意差は認めなかった．大腸癌組織における各遺伝子発現と臨
床病理学的特徴との関係では，IGFBP-3 遺伝子の高発現がリンパ節転移に有意に関係していた (P=0.035)．生存との関係では，IGFBP-3 遺伝子高発現群は低発現群と比較して有意に不良であっ た(P=0.003)．生存における多変量解析では，リンパ節転移および肝転移とともに IGFBP-3 遺伝子発 現は独立した予後因子であった(それぞれ P=0.011, P<0.001, P=0.026)． 【考察】本研究では大腸癌の癌組織および隣接正常粘膜におけるIGF ファミリー遺伝子の mRNA 発 現レベルを測定し、発現レベルと臨床病理学的特徴および臨床転帰との関連を検討し，IGFBP-3 遺 伝子発現は独立した予後予測因子として抽出された． IGFBP-3 の発現と予後に関して，肝細胞癌患者や舌癌患者においては，IGFBP-3 の高発現は良 好な生存と関連していたとの報告がある(Aishima et al., 2006, Papadimitrakopoulou et al., 2006)
が，大腸癌組織におけるこれまでの報告では，IGFBP-3 遺伝子の高発現は，大腸癌の急速な増殖と
予後不良に関連していたと報告されている(Vestey et al., 2005, Sheen-Chen et al., 2009)．乳癌で
は免疫組織化学的研究において，IGFBP-3 の高発現はより短い生存期間と関連していると報告されて
おり(Kim et al., 2010)，IGFBP-3 遺伝子に関しても，高発現患者では生存期間が不良であった(Yu et al., 1998)．さらに神経膠芽腫の患者においても，腫瘍組織における IGFBP-3 の過剰発現は，強力 な独立した予測因子であったと報告されている(Santosh et al., 2010)．
癌においてIGFBP-3 高発現が予後不良となるメカニズムに関しては，十分には解明されていない．
過去の報告を見ると，Matrigel を用いて血管を皮下移植した in vivo の実験で，IGFBP-3 の用量依
存的に新生血管の形成が見られ、IGFBP-3 が血管新生を促進し，VEGF などの血管新生促進分子
の発現を調節することが報告されており(Granata et al., 2007)、in vitro の実験では乳癌細胞におい
て，EGFR のリン酸化と MAP キナーゼ経路の活性化を介した EGF のシグナル伝達による癌細胞の
増殖作用をIGFBP-3 が増幅し、IGFBP-3 は SphK1 によって媒介される EGFR シグナル伝達を増 加させることによって乳癌細胞の増殖を促進することが報告されている(Martin et al., 2003, Martin et al., 2014)．すなわち今回我々の結果で IGFBP-3 高発現が大腸癌の予後不良因子となったメカニ ズムの一つとして，IGFBP-3 が SphK1 によって媒介される EGFR のシグナル伝達を活性化し，MAP
キナーゼシグナル伝達経路によってVEGF を誘導することで血管新生を促進したためと考えられた．
【結論】本研究では大腸癌術後患者において，大腸癌組織のIGFBP-3 遺伝子発現は，独立した予後
予測因子として有用である可能性が示唆された．
【引用文献】
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論文目録
Ⅰ 主論文
Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is a useful predictor of outcomes in patients with colorectal cancer.
Yamamoto, N., Oshima, T., Yoshihara, K., Aoyama, T., Hayashi, T., Yamada, T., Sato, T., Shiozawa, M., Yoshikawa, T., Morinaga, S., Rino, Y., Kunisaki, C., Tanaka, K., Akaike, M., Imada, T., Masuda, M.:
Oncology Letters Vol.13, No.5, Page3958-3966, 2017
Ⅱ 副論文
Reduced expression of the AdipoR1 gene is correlated with venous invasion in colorectal cancer.
NYamamoto, N., Oshima, T., Yoshihara, K., Sato, T., Yamada, R., Fujii, S., Nagano, Y., Shiozawa, M., Akaike, M., Wada, N., Rino, Y., Kunisaki, C., Masuda, M., Tanaka, K., Imada, T.:
Molecular Medicine Reports Vol.2, No.4, Page555-559, 2009
Impact of body mass index and visceral adiposity on outcomes in colorectal cancer. Yamamoto, N., Fujii, S., Sato, T., Oshima, T., Rino, Y., Kunisaki, C., Masuda, M., Imada, T.:
Asia-Pacific Journal of Clinical Oncology Vol.8, No.4, Page337-345, 2012
Upper abdominal body shape is the risk factor for postoperative pancreatic fistula after splenectomy for advanced gastric cancer: a retrospective study.
Yamamoto N, Oshima T, Sato T, Makino H, Nagano Y, Fujii S, Rino Y, Imada T, Kunisaki C.：
Ⅲ 参考論文
1 Risk factors for 6-month continuation of S-1 adjuvant chemotherapy for resected pancreatic cancer.
Aoyama, T., Katayama, Y., Murakawa, M., Asari, M., Kanazawa, A., Higuchi, A., Shiozawa, M., Kobayashi, S., Ueno, M., Morimoto, M., Ohkawa, S., Akaike, M., Yamamoto, N., Yoshikawa, T., Rino, Y., Masuda, M. & Morinaga, S.:
Cancer chemotherapy and pharmacology, Vol.74, No.6, Page 1235-1240,2014. 2 Safety and feasibility of S-1 adjuvant chemotherapy for pancreatic cancer in elderly patients.
Aoyama, T., Katayama, Y., Murakawa, M., Atsumi, Y., Yamaoku, K., Kanazawa, A., Higuchi, A., Shiozawa, M., Kobayashi, S., Ueno, M., Morimoto, M., Yamamoto, N., Oshima, T., Yoshikawa, T., Rino, Y., Masuda, M. & Morinaga, S.:
Cancer chemotherapy and pharmacology, Vol.75, No.6, Page 1115-20,2015. 3 Clinical implication of peritoneal cytology in the pancreatic cancer patients who underwent curative resection followed by adjuvant gemcitabine or S-1 chemotherapy. Aoyama, T., Katayama, Y., Murakawa, M., Shiozawa, M., Morimoto, M., Yamamoto, N., Yoshikawa, T., Rino, Y., Masuda, M. & Morinaga, S.:
Hepatogastroenterology, Vol.62, No.137, Page 200-6,2015.
4 Impact of postoperative complications on survival and recurrence in pancreatic cancer. Aoyama, T., Murakawa, M., Katayama, Y., Yamaoku, K., Kanazawa, A., Higuchi, A., Shiozawa, M., Morimoto, M., Yoshikawa, T., Yamamoto, N., Rino, Y., Masuda, M., Morinaga, S.:
Anticancer Research, Vol.35, No.4, Page 2401-9,2015.
5 Effectiveness of alendronate for bone disorder after gastrectomy for gastric cancer. Atsumi, Y., Rino, Y., Sato, T., Cho, H., Yoshikawa, T., Yamamoto, N., Oshima, T., Yukawa, N., Shiozawa, M., Morinaga, S., Masuda, M.:
6 Clinical significance of platelet-derived growth factor receptor-beta gene expression in stage II/III gastric cancer with S-1 adjuvant chemotherapy.
Higuchi, A., Oshima, T., Yoshihara, K., Sakamaki, K., Aoyama, T., Suganuma, N., Yamamoto, N., Sato, T., Cho, H., Shiozawa, M., Yoshikawa, T., Rino, Y., Kunisaki, C., Imada, T., Masuda, M.:
Oncology Letters, Vol.13, No.2, Page 905-911,2017.
7 Overexpression of tissue inhibitor of metalloproteinase-1 gene correlates with poor outcomes in colorectal cancer.
Inagaki, D., Oshima, T., Yoshihara, K., Tamura, S., Kanazawa, A., Yamada, T., Yamamoto, N., Sato, T., Shiozawa, M., Morinaga, S., Akaike, M., Fujii, S., Numata, K., Kunisaki, C., Rino, Y., Tanaka, K., Masuda, M. Imada, T.:
Anticancer Research, Vol.30, No.10, Page 4127-30,2010.
8 Relation of MT1-MMP gene expression to outcomes in colorectal cancer.
Kanazawa, A., Oshima, T., Yoshihara, K., Tamura, S., Yamada, T., Inagaki, D., Sato, T., Yamamoto, N., Shiozawa, M., Morinaga, S., Akaike, M., Kunisaki, C., Tanaka, K., Masuda, M., Imada, T.:
Journal of Surgical Oncology, Vol.102, No.6, Page 571-5,2010.
9 Predictive factors for surgical complications of laparoscopy-assisted distal gastrectomy for gastric cancer.
Kunisaki, C., Makino, H., Takagawa, R., Sato, K., Kawamata, M., Kanazawa, A., Yamamoto, N., Nagano, Y., Fujii, S., Ono, H. A., Akiyama, H., Shimada, H.:
Surgical Endoscopy, Vol.23, No.9, Page 2085-93,2009.
10 Prospective randomized controlled trial comparing the use of 3.5-mm and 4.8-mm staples in gastric surgery.
Kunisaki, C., Makino, H., Takagawa, R., Yamamoto, N., Nagano, Y., Fujii, S., Kosaka, T., Ono, H. A., Akiyama, H., Shimada, H.:
11 Surgical outcomes in esophageal cancer patients with tumor recurrence after curative esophagectomy.
Kunisaki, C., Makino, H., Takagawa, R., Yamamoto, N., Nagano, Y., Fujii, S., Kosaka, T., Ono, H. A., Otsuka, Y., Akiyama, H., Ichikawa, Y., Shimada, H.:
Journal of Gastrointestinal Surgery, Vol.12, No.5, Page 802-10,2008.
12 Learning curve for laparoscopy-assisted distal gastrectomy with regional lymph node dissection for early gastric cancer.
Kunisaki, C., Makino, H., Yamamoto, N., Sato, T., Oshima, T., Nagano, Y., Fujii, S., Akiyama, H., Otsuka, Y., Ono, H. A., Kosaka, T., Takagawa, R., Shimada, H.:
Surgical Laparoscopy Endoscopy & Percutaneous Techniques, Vol.18, No.3, Page 236-41,2008.
13 The short- and long-term outcomes of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas.
Murakawa, M., Aoyama, T., Asari, M., Katayama, Y., Yamaoku, K., Kanazawa, A., Higuchi, A., Shiozawa, M., Kobayashi, S., Ueno, M., Morimoto, M., Yamamoto, N., Yoshikawa, T., Rino, Y., Masuda, M., Morinaga, S.:
BMC surgery, Vol.15, 120,2015.
14 Clinical implications of dihydropyrimidine dehydrogenase expression in patients with pancreatic cancer who undergo curative resection with S-1 adjuvant chemotherapy. Murakawa, M., Aoyama, T., Miyagi, Y., Atsumi, Y., Kazama, K., Yamaoku, K., Kanazawa, A., Shiozawa, M., Kobayashi, S., Ueno, M., Morimoto, M., Yamamoto, N., Oshima, T., Yoshikawa, T., Rino, Y., Masuda, M., Morinaga, S.:
Oncology Letters, Vol.14, No.2, Page 1505-1511,2017. 15 The clinical significance of SWI/SNF complex in pancreatic cancer.
Numata, M., Morinaga, S., Watanabe, T., Tamagawa, H., Yamamoto, N., Shiozawa, M., Nakamura, Y., Kameda, Y., Okawa, S., Rino, Y., Akaike, M., Masuda, M., Miyagi, Y.:
16 Relationship between RegIV gene expression to outcomes in colorectal cancer. Numata, M., Oshima, T., Yoshihara, K., Watanabe, T., Tsuchida, K., Tamagawa, H., Yamamoto, N., Shiozawa, M., Morinaga, S., Akaike, M., Kunisaki, C., Rino, Y., Tanaka, K., Masuda, M., Imada, T.:
Journal of Surgical Oncology, Vol.104, No.2, Page 205-9,2011.
17 The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease.
Numata, M., Shiozawa, M., Watanabe, T., Tamagawa, H., Yamamoto, N., Morinaga, S., Watanabe, K., Godai, T., Oshima, T., Fujii, S., Kunisaki, C., Rino, Y., Masuda, M., Akaike, M.:
World Journal of Surgical Oncology, Vol.10, 109,2012.
18 Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer.
Oshima, T., Akaike, M., Yoshihara, K., Shiozawa, M., Yamamoto, N., Sato, T., Akihito, N., Nagano, Y., Fujii, S., Kunisaki, C., Wada, N., Rino, Y., Tanaka, K., Masuda, M., Imada, T.:
International Journal of Oncology, Vol.33, No.3, Page 573-7,2008.
19 Clinicopathological significance of the gene expression of matrix metalloproteinases and reversion-inducing cysteine-rich protein with Kazal motifs in patients with colorectal cancer: MMP-2 gene expression is a useful predictor of liver metastasis from colorectal cancer.
Oshima, T., Kunisaki, C., Yoshihara, K., Yamada, R., Yamamoto, N., Sato, T., Makino, H., Yamagishi, S., Nagano, Y., Fujii, S., Shiozawa, M., Akaike, M., Wada, N., Rino, Y., Masuda, M., Tanaka, K., Imada, T.:
Oncology Reports, Vol.19, No.5, Page 1285-91,2008.
20 Reduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancer.
Oshima, T., Kunisaki, C., Yoshihara, K., Yamada, R., Yamamoto, N., Sato, T., Makino, H., Yamagishi, S., Nagano, Y., Fujii, S., Shiozawa, M., Akaike, M., Wada, N., Rino, Y.,
Masuda, M., Tanaka, K., Imada, T.:
Oncology Reports, Vol.19, No.4, Page 953-9,2008.
21 Relation of INHBA gene expression to outcomes in gastric cancer after curative surgery.
Oshima, T., Yoshihara, K., Aoyama, T., Hasegawa, S., Sato, T., Yamamoto, N., Akito, N., Shiozawa, M., Yoshikawa, T., Numata, K., Rino, Y., Kunisaki, C., Tanaka, K., Akaike, M., Imada, T., Masuda, M.:
Anticancer research, Vol.34, No.5, Page 2303-9,2014.
22 Technique and assessment of sentinel lymph node biopsy usefulness in laparoscopy-assisted distal gastrectomy.
Rino, Y., Takanashi, Y., Harada, H., Ashida, A., Saeki, H., Yukawa, N., Kanari, M., Satoh, T., Yamamoto, N., Yamada, R., Imada, T.:
Surgical Endoscopy, Vol.20, No.12, Page 1887-91,2006.
23 A phase I study of bi-weekly combination therapy with S-1 and docetaxel for advanced or recurrent gastric cancer.
Rino, Y., Takanashi, Y., Yukawa, N., Saeki, H., Wada, H., Kanari, M., Yamada, R., Satoh, T., Yamamoto, N., Imada, T.:
Anticancer Research, Vol.26, No.2B, Page 1455-62,2006.
24 Vitamin E deficiency begins within 6 months after gastrectomy for gastric cancer. Rino, Y., Yukawa, N., Sato, T., Yamamoto, N., Tamagawa, H., Hasegawa, S., Hayashi, T., Atsumi, Y., Oshima, T., Yoshikawa, T., Masuda, M., Imada, T.:
World journal of surgery, Vol.38, No.8, Page 2065-9,2014.
25 Using NU-KNIT(R) for hemostasis around recurrent laryngeal nerve during transthoracic esophagectomy with lymphadenectomy for esophageal cancer.
Rino, Y., Yukawa, N., Sato, T., Yamamoto, N., Tamagawa, H., Hasegawa, S., Oshima, T., Yoshikawa, T., Masuda, M., Imada, T.:
26 Visualization of blood supply route to the reconstructed stomach by indocyanine green fluorescence imaging during esophagectomy.
Rino, Y., Yukawa, N., Sato, T., Yamamoto, N., Tamagawa, H., Hasegawa, S., Oshima, T., Yoshikawa, T., Masuda, M., Imada, T.:
BMC medical imaging, Vol.14, 18,2014.
27 Phase II Study of S-1 Monotherapy as a First-line, Combination Therapy of S-1 plus Cisplatin as a Second-line, and Weekly Paclitaxel Monotherapy as a Third-line Therapy in Patients with Advanced Gastric Carcinoma: Phase II Study of S-1, S-1 plus Cisplatin, and Weekly Paclitaxel in Patients with Advanced Gastric Carcinoma.
Rino, Y., Yukawa, N., Wada, N., Suzuki, M., Murakami, H., Yamada, T., Nakayama, H., Yamamoto, N., Sato, T., Yamada, R., Ohshima, T., Masuda, M., Imada, T.:
Clinical Medicine Insights. Oncology, Vol.2, 375-83,2008.
28 Impact of preoperative hand grip strength on morbidity following gastric cancer surgery.
Sato, T., Aoyama, T., Hayashi, T., Segami, K., Kawabe, T., Fujikawa, H., Yamada, T., Yamamoto, N., Oshima, T., Rino, Y., Masuda, M., Ogata, T., Cho, H., Yoshikawa, T.
Gastric Cancer, Vol.19, No.3, Page 1008-15,2016.
29 Clinical significance of SPARC gene expression in patients with gastric cancer.
Sato, T., Oshima, T., Yamamoto, N., Yamada, T., Hasegawa, S., Yukawa, N., Numata, K., Kunisaki, C., Tanaka, K., Shiozawa, M., Yoshikawa, T., Akaike, M., Rino, Y., Imada, T., Masuda, M.:
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30 Overexpression of the fibroblast growth factor receptor-1 gene correlates with liver metastasis in colorectal cancer.
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