Abstract
BackgroundDrug resistance is one of the major concerns in the treatment of hepatocellular carcinoma (HCC). The aim of the present study was to determine whether aberrant high expression of the inhibitor of differentiation 1(ID1) confers oxaliplatin-resistance to HCC by activating the pentose phosphate pathway (PPP).MethodsAberrant high expression of ID1 was detected in two oxaliplatin-resistant cell lines MHCC97H–OXA(97H–OXA) and Hep3B–OXA(3B–OXA). The lentiviral shRNA or control shRNA was introduced into the two oxaliplatin-resistant cell lines. The effects of ID1 on cell proliferation, apoptosis and chemoresistance were evaluated in vitro and vivo. The molecular signaling mechanism underlying the induction of HCC proliferation and oxaliplatin resistance by ID1 was explored. The prognostic value of ID1/G6PD signaling in HCC patients was assessed using the Cancer Genome Atlas (TCGA) database.ResultsID1 was upregulated in oxaliplaitin-resistant HCC cells and promoted HCC cell proliferation and oxaliplatin resistance. Silencing ID1 expression in oxaliplaitin-resistant HCC cell lines inhibited cell proliferation and sensitized oxaliplaitin-resistant cells to death. ID1 knockdown significantly decreased the expression of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme of the PPP. Silencing ID1 expression blocked the activation of G6PD, decreased the production of PPP NADPH, and augmented reactive oxygen and species (ROS), thus inducing cell apoptosis. Study of the molecular mechanism showed that ID1 induced G6PD promoter transcription and activated PPP through Wnt/β-catenin/c-MYC signaling. In addition, ID1/G6PD signaling predicted unfavorable prognosis of HCC patients on the basis of TCGA.ConclusionsOur study provided the first evidence that ID1 conferred oxaliplatin resistance in HCC by activating the PPP. This newly defined pathway may have important implications in the research and development of new more effective anti-cancer drugs.
Highlights
Drug resistance is one of the major concerns in the treatment of hepatocellular carcinoma (HCC)
We found that high expression of inhibitor of differentiation and DNA binding-1 (ID1) promoted HCC cell proliferation and conferred oxaliplatin resistance to HCC by regulating glucose-6-phosphate dehydrogenase (G6PD), a key enzyme of pentose phosphate pathway, which may represent a novel target to improve the therapeutic efficacy of patients with advanced HCC
ID1 is up-regulated in oxaliplaitin-resistant HCC cell lines and involved in HCC cell malignant proliferation, apoptosis and chemoresistance in vitro It was found in our previous study that oxaliplaitinresistant HCC cells acquired stem cell-like traits, and gene profile analysis revealed 267 up-regulated and 65 down-regulated genes in oxaliplatin-treated HCC tumors, compared with GS-treated HCC tumors [14]
Summary
Drug resistance is one of the major concerns in the treatment of hepatocellular carcinoma (HCC). Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the major cause of cancerrelated death [1]. Transcatheter arterial chemoembolization (TACE) or systemic chemotherapy may improve the survival of patients with advanced HCC [3], but acquired drug resistance remains an obstacle in further improving the postoperative outcome of HCC patients. Oxaliplatin, a third-generation platinum analogue, is a compound with significant anti-cancer activities against colorectal, breast, gastric, renal carcinomas and sarcomas [4]. It has been employed in combination with 5-fluorouracil (5-FU) and leucovorin as the first-line chemotherapy regimen (FOLFOX4) for advanced HCC [5]. Molecular mechanisms involved in oxaliplatin resistance of HCC remain poorly defined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
