Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells

• Published in: Carcinogenesis (New York) Vol. 41; no. 11; pp. 1616 - 1623
• Main Authors: Nishimura, Sadaaki, Yashiro, Masakazu, Sera, Tomohiro, Yamamoto, Yurie, Kushitani, Yukako, Sugimoto, Atsushi, Kushiyama, Shuhei, Togano, Shingo, Kuroda, Kenji, Okuno, Tomohisa, Murakami, Yoshiki, Ohira, Masaichi
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 13.11.2020
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgaa031

Abstract Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. A reason for the poor prognosis of SGC is that the driver gene responsible for SGC has not been identified. To identify the characteristic driver gene of SGC, we examined the genomic landscape of six human SGC cell lines of OCUM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12 and OCUM-14, using multiplex gene panel testing by next-generation sequencing. In this study, the non-synonymous mutations of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) gene were detected in OCUM-12, OCUM-2M and OCUM-14 among the six SGC cell lines. Capillary sequencing analysis confirmed the non-sense or missense mutation of STK11/LKB1 in the three cell lines. Western blot analysis showed that LKB1 expression was decreased in OCUM-12 cells and OCUM-14 cells harboring STK11/LKB1 mutation. The mammalian target of rapamycin (mTOR) inhibitor significantly inhibited the proliferation of OCUM-12 and OCUM-14 cells. The correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were examined using 708 primary gastric carcinomas by immunochemical study. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth and frequent nodal involvement, in compared with the high STK11/LKB1 expression group. Collectively, our study demonstrated that STK11/LKB1 mutation might be responsible for the progression of SGC, and suggested that mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for patients with SGC. (i) STK11/LKB1 was mutated in three of six SGC cell lines. (ii) Low STK11/LKB1 expression level was recognized in most of patients with SGC. (iii) The mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for this intractable disease of SGC.