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S5-5
STK24 driven tumor progression is associated with loss of SMAD4 and promotion of autophagy in PDAC.
Kuang-Hung Cheng
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 804. |
Pancreatic cancer is one of the most lethal malignancy with the highest mortality rate of all types of cancers. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of f malignant pancreatic cancer, and is characterized by the mutations of KRAS (95%), INK4a (90%), P53 (50%) and SMAD4 (45%). Identification of novel PDAC oncogenes may provide new avenues for identify potential diagnostic markers and therapeutic targets for the treatment of PDAC. STK24, a mammalian STE20-like serine/threonine protein kinases family member, also named Mammalian STE20-like protein kinase 3 (MST-3), is known to induce cell growth and promote tumor development. However, the role of STK24 in pancreatic development and carcinogenesis to be determined. To study the pathological role of STK24 in PDAC, here we reported that STK24expression can be induced in PDAC cells by TGF��1 stimulation in vitro and its up-regulation directly correlated with advanced stages and SMAD4 expression status of PDAC. Consequently, we used shRNA to knockdown STK24 expression and demonstrated that STK24 is associated with TGF��1/Smad4 signaling pathway, cell cycle progression and EMT program in PDAC. Furthermore, we generated novel mutant mice that enable inactivation of STK24 in the context of our well-characterized Pdx-1CreKrasG12D or/and Pdx-1CreKrasG12D p53L/L PDAC models. We found that STK24 loss halted Kras induced pancreatic carcinogenic in mice. Mechanistically, loss of STK24 in PDAC is likely to inhibit the autophagy during Kras driven pancreatic intra-neoplastic lesions (PanINs) formation, and may lead to prevent the formation and development of PDAC. Thus, the identification of STK24 network components that are essential for tumorigenic growth of PDAC will subsequently be used in the design of preclinical trials that employ therapeutics to target PDAC.
Key words：PDAC，STK24，Autophagy，GEM models. |
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