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• 札幌医科大学   腫瘍内科   診療医  

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• Modulation of Epithelial-Mesenchymal Transition Is a Possible Underlying Mechanism for Inducing Chemoresistance in MIA PaCa-2 Cells against Gemcitabine and Paclitaxel.

  Hajime Nakamura, Megumi Watanabe, Kohichi Takada, Tatsuya Sato, Fumihito Hikage, Umetsu A, Muramatsu J, Masato Furuhashi, Ohguro H

  Biomedicines    2024年05月

  　概要を見る

  To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

  DOI PubMed

• Gap junction beta‐4 accelerates cell cycle progression and metastasis through MET–AKT activation in pancreatic cancer

  Joji Muramatsu, Yohei Arihara, Makoto Yoshida, Tomohiro Kubo, Hajime Nakamura, Kazuma Ishikawa, Hiromi Fujita, Shintaro Sugita, Takumi Konno, Takashi Kojima, Yutaka Kawano, Masayoshi Kobune, Kohichi Takada

  Cancer Science    2024年02月

  　概要を見る

  AbstractDespite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta‐4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G0/G1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT‐2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET–AKT activities. Such data suggest that targeting the GJB4–MET axis could represent a promising new therapeutic strategy for pancreatic cancer.

  DOI

• Clinical characterization of patients with g<i>BRCA1/2</i> mutation-positive unresectable pancreatic cancer: a multicenter prospective study

  Tomohiro Kubo, Joji Muramatsu, Yohei Arihara, Ayako Murota, Kazuma Ishikawa, Makoto Yoshida, Hiroyuki Nagashima, Fumito Tamura, Yuki Ikeda, Makoto Usami, Michihiro Ono, Hajime Nakamura, Daichi Watanabe, Takanori Shibata, Kaoru Kasahara, Akihiro Sakurai, Kohichi Takada

  Japanese Journal of Clinical Oncology    2024年01月

  　概要を見る

  Abstract Background Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan. Methods & Results In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0–9.2). Conclusions The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies. An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting.

  DOI

• 経直腸超音波内視鏡下穿刺生検術で診断し得た骨髄脂肪腫の１例

  貴之 今川, 丈児 村松, 咲貴 飴田, 亮 伊藤, 潤也 佐賀, 敬典 柴田, さや香 野田, 佑機 上小倉, 祐司 西川, 博士 村松

  日本消化器内視鏡学会雑誌    2023年

  DOI

• Complete Response Induced by Concurrent Chemoradiotherapy in a Patient with NUT Carcinoma

  Joji Muramatsu, Kohichi Takada, Shintaro Sugita, Takaaki Tsuchiya, Keisuke Yamamoto, Masaru Takagi, Kazuyuki Murase, Saki Ameda, Yohei Arihara, Koji Miyanishi, Koh-Ichi Sakata, Junji Kato

  Internal Medicine ( Japanese Society of Internal Medicine )  61 ( 8 ) 1299 - 1304  2022年04月

  DOI

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