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

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.

EMMPRIN in extracellular vesicles from peritoneal mesothelial cells stimulates the invasion activity of diffuse-type gastric cancer cells

“…Scirrhous-type gastric cancer (SGC), an aggressive malignant subtype of diffuse-type GC [3], often shows frequent peritoneal metastasis that results in an extremely poor prognosis compared to other types of GC [4]. One of the reasons for the poor prognosis of diffuse-type GC is the deficiency of efficient therapeutic targets based on the molecular mechanisms of peritoneal metastasis in this type of GC [5].…”

Clinicopathological and prognostic significance of LKB1 expression in gastric cancer: A systematic review and meta-analysis

“…Among the 11 studies, 10 were from China, and one was from Japan, with sample sizes ranging from 60 to 708. Overall, the meta-analysis included 1,767 patients with GC [3,14,15,[20][21][22][23][24][25][26][27]. LKB1 staining was performed using immunohistochemical methods, and the detailed characteristics are shown in Table 1.…”

The Genomic Signatures of Linitis Plastica Signal the Entrance into a New Era: Novel Approaches for Diagnosis and Treatment

“…Last but not least, CD 63, an exosome associated with extracellular communication, possesses a significant role in tumor prognosis, due to its correlation with scirrhous cancer, patients aged over 65, a tumor depth of T3 or T4, lymphatic metastasis and a tumor size of over 5 cm [18]. Loss of function in the STK11 or LKB1 tumor suppressor genes, as well as CD44-IGF1R fusion, or the up-regulation of NOS3 and ARHGAP4 also leads to LP, increases nodal involvement and promotes epithelial mesenchymal transition through the MAPK pathway [16,20,21]. The up-regulation of ARHGAP4 activates MMP2 and MMP9 metalloproteinases and decreases the expression of E-Cadherin and Claudin-1, thereby promoting the distinctive invasive pattern of LP [16].…”

“…Moreover, the overexpression of FGF-18 is regulated by its target, miR-590-5p, making it a potential target [10]. The AMPK pathway, IGF2BP3, IGF1R, MUC16, ARHGAP4, Her-2, MET and mTOR signaling from STKI11/LKB1 are also possible targets [3,10,20,21,30]. Specifically, IGF1R has anti-apoptotic action, and ARHGAP4 is directly associated with the down-regulation of E-cadherin and Claudin 1, making them potent targets [16,21].…”