Hepatocellular carcinoma (HCC) is a major leading cause of cancer-related death worldwide. Alpha fetoprotein (AFP) is reactivated in a majority of hepatocellular carcinoma (HCC) and associated with poor patient outcomes. Although increasing evidence has shown that AFP can regulate HCC cell growth, the precise functions of AFP in hepatocarcinogenesis and the associated underlying mechanism remain incompletely understood. In this study, we demostrated that depleting AFP significantly suppressed diethylnitrosamine (DEN)-induced liver tumor progression in an AFP gene-deficient mouse model. Similarly, knocking down AFP expression inhibited human HCC cell proliferation and tumor growth by inducing apoptosis. AFP expression level was inversely associated with the apoptotic rate in mouse and human HCC specimens. Investigation of potential cross-talk between AFP and apoptotic signaling revealed that AFP exerted its growth-promoting effect by suppressing the Fas/FADD-mediated extrinsic apoptotic pathway. Mechanistically, AFP bound to the RNA-binding protein HuR, increasing the accumulation of HuR in the cytoplasm and subsequent inhibition of Fas mRNA translation. In addition, we found that inhibiting AFP enhanced the cytotoxicity of therapeutics to AFP-positive HCC cells by activating HuR-mediated Fas/FADD apoptotic signaling. Conclusion: Our study defined the pro-oncogenic role of AFP in HCC progression and uncovered a novel antiapoptotic mechanism connecting AFP to HuR-mediated Fas translation. Our findings suggest that AFP is involved in the pathogenesis and chemosensitivity of HCC and that blockade of AFP may be a promising strategy to treat advanced HCC.
Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.
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