Tomihara Hideo, Yamada Daisaku, Eguchi Hidetoshi, Iwagami Yoshifumi, Noda Takehiro, Asaoka Tadafumi, Wada Hiroshi, Kawamoto Koichi, Gotoh Kunihito, Takeda Yutaka, Tanemura Masahiro, Mori Masaki, Doki Yuichiro
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan.
Cancer Sci. 2017 Mar;108(3):398-407. doi: 10.1111/cas.13159.
Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c-Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c-Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c-Met expression, and these cells may exacerbate patients' prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c-Met expression; moreover, high c-Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c-Met upregulation in PDAC cells. We established GEM-resistant and radioresistant PDAC cells to analyze the transcriptome involved in c-Met expression. The microarray data for the established radiation-resistant PDAC cells indicated miR-181b-5p downregulation, which targets ETS1, one of the transcription factors for c-Met, and it was shown that radiation exposure induced c-Met expression through ETS1 increase by the suppression of miR-181b-5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.
胰腺导管腺癌（PDAC）的术前放化疗（CRT）已成为一种显示出良好预后影响的合理策略。然而，术前CRT后，切除的标本显示有残留肿瘤细胞，这表明一些肿瘤细胞已获得或被选择为对CRT耐药。最近，两种肿瘤学机制，即上皮-间质转化（EMT）和癌症干细胞（CSC）的存在，被报道与多种癌症的耐药性有关。先前的报告显示，肝细胞生长因子（HGF）可诱导PDAC细胞发生EMT；此外，HGF受体c-Met被确定为主要的胰腺CSC标志物。然而，c-Met表达的临床意义仍不清楚。因此，我们推测CRT后残留的PDAC组织可能含有高表达c-Met的细胞，这些细胞可能会使患者的预后恶化。在免疫组织化学分析中，我们发现术前CRT与高c-Met表达显著相关；此外，高c-Met表达是预后不良的重要标志物。接下来，我们研究了PDAC细胞中c-Met上调的机制。我们建立了吉西他滨耐药和放射耐药的PDAC细胞，以分析参与c-Met表达的转录组。所建立的放射耐药PDAC细胞的微阵列数据表明，靶向c-Met转录因子之一ETS1的miR-181b-5p表达下调，并且显示辐射暴露通过抑制miR-181b-5p导致ETS1增加从而诱导c-Met表达。这些结果表明，针对这些机制可能会促进一种新的多学科治疗策略的发展，以提高术前CRT的效率。
