Abstract
Though midline1 interacting protein 1 (MID1IP1) was known as one of the glucose-responsive genes regulated by carbohydrate response element binding protein (ChREBP), the underlying mechanisms for its oncogenic role were never explored. Thus, in the present study, the underlying molecular mechanism of MID1P1 was elucidated mainly in HepG2 and Huh7 hepatocellular carcinoma cells (HCCs). MID1IP1 was highly expressed in HepG2, Huh7, SK-Hep1, PLC/PRF5, and immortalized hepatocyte LX-2 cells more than in normal hepatocyte AML-12 cells. MID1IP1 depletion reduced the viability and the number of colonies and also increased sub G1 population and the number of TUNEL-positive cells in HepG2 and Huh7 cells. Consistently, MID1IP1 depletion attenuated pro-poly (ADP-ribose) polymerase (pro-PARP), c-Myc and activated p21, while MID1IP1 overexpression activated c-Myc and reduced p21. Furthermore, MID1IP1 depletion synergistically attenuated c-Myc stability in HepG2 and Huh7 cells. Of note, MID1IP1 depletion upregulated the expression of ribosomal protein L5 or L11, while loss of L5 or L11 rescued c-Myc in MID1IP1 depleted HepG2 and Huh7 cells. Interestingly, tissue array showed that the overexpression of MID1IP1 was colocalized with c-Myc in human HCC tissues, which was verified in HepG2 and Huh7 cells by Immunofluorescence. Notably, depletion of CCR4-NOT2 (CNOT2) with adipogenic activity enhanced the antitumor effect of MID1IP1 depletion to reduce c-Myc, procaspase 3 and pro-PARP in HepG2, Huh7 and HCT116 cells. Overall, these findings provide novel insight that MID1IP1 promotes the growth of liver cancer via colocalization with c-Myc mediated by ribosomal proteins L5 and L11 and CNOT2 as a potent oncogenic molecule.
Highlights
Though hepatocellular carcinoma (HCC) is reported to be the sixth most common cancer in the world according 2018 Global Cancer Statistics [1], more effective therapies are still being required compared to classical treatments such as chemotherapy with a kinase inhibitor sorafenib [2,3], surgery [4], immunotherapy [1] and liver transplantation [5]
HCCs, elucidated in association with c-Myc mediated by ribosomal protein L5 or L11 and CNOT2 in HCCs, with the asas a potent oncogene in with the hypothesis hypothesis that that midline1 interacting protein 1 (MID1IP1)
Further study is required to evaluate the pivotal roles and protein–protein interaction (PPI) of MID1IP1 and CNOT2 in cancers via the Warburg effect in vitro and in vivo. These findings provide novel insight that MID1IP1 promotes the growth of liver cancer via colocalization with c-Myc mediated by ribosomal protein L5 and L11 and CNOT2 as a potent oncogenic molecule
Summary
Though hepatocellular carcinoma (HCC) is reported to be the sixth most common cancer in the world according 2018 Global Cancer Statistics [1], more effective therapies are still being required compared to classical treatments such as chemotherapy with a kinase inhibitor sorafenib [2,3], surgery [4], immunotherapy [1] and liver transplantation [5]. Myc is elevated or dysregulated in approximately 70% of human cancers, including HCC [8,9]. The MYC oncogene family comprising of C-MYC, MYCN and MYCL encode c-Myc, N-Myc and L-Myc, which are involved in ribosome biogenesis, cell-cycle progression, protein translation and metabolism, with a variety of biological functions including proliferation, differentiation, survival and immune surveillance [10]. Myc is known to regulate ribosome biogenesis and protein synthesis through the transcriptional control of RNA and protein components of ribosomes [11]
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