Transgelin-2 is a novel target of KRAS-ERK signaling involved in the development of pancreatic cancer

• Published in: Journal of experimental & clinical cancer research Vol. 37; no. 1; p. 166
• Main Authors: Sun, Yan, Peng, Wenfang, He, Weiwei, Luo, Man, Chang, Guilin, Shen, Jiping, Zhao, Xiaoping, Hu, Yu
• Format: Journal Article
• Language: English
• Published: England BioMed Central 24.07.2018; BMC
• Subjects: Aged; Amino Acid Sequence; Animals; Breast cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell growth; Cell Proliferation - physiology; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; HEK293 Cells; Heterografts; Humans; Kinases; KRAS; Lymphatic system; Male; MAP Kinase Signaling System; Medical prognosis; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Microfilament Proteins - biosynthesis; Microfilament Proteins - genetics; MicroRNAs; Middle Aged; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Mutation; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Patients; PDAC; Phosphorylation; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Smooth muscle; Transfection; Transgelin-2; Tumorigenesis; Up-Regulation; KRAS; PDAC; Transgelin-2; ERK
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-018-0818-z

The KRAS mutation is the driving force of pancreatic ductal adenocarcinoma (PDAC). Downstream effectors of KRAS signal pathways are crucial to the development of PDAC. The purpose of this study was to investigate the relationship between KRAS mutation and transgelin-2. Transgelin-2 is highly expressed in PDAC tissues compared with adjacent normal tissues. The underlying mechanism for upregulating transgelin-2 is largely unknown. Expression of transgelin-2 was analyzed by microarray data and qRT-PCR. The effect of KRAS signaling on transgelin-2 expression was examined in PDAC cells in the presence or absence of the ERK inhibitor. The interaction of transgelin-2 with ERK was confirmed by immunoprecipitation. ERK-mediated Phosphorylation of transglein-2 was detected by in vivo and in vitro kinase assays. The gain-of-function and loss-of-function approaches were used to examine the role of phosphorylation of transgelin-2 on cell proliferation. Phosphorylation of transgelin-2 was detected by immunohistochemistry in PDAC tissues. Here we found transgelin-2 expression was induced by KRAS mutation. In the case of KRAS mutation, ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC. In addition, S145 phosphorylation of transgelin-2 was associated with a poor prognosis in patients with PDAC. This study indicated that KRAS-ERK-mediated transeglin-2 phosphorylation played an important role in the development of PDAC. Inhibition of transgelin-2 phosphorylation may be a potential therapeutic strategy for targeting PDAC with KRAS mutation.