Effects of LRP1B Regulated by HSF1 on Lipid Metabolism in Hepatocellular Carcinoma

Miaomiao Li,1,* Juntao Hu,2,* Riming Jin,3,* Hongxia Cheng,1 Huaping Chen,4 Limin Li,4 Kun Guo1 1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People’s Republic of China; 2Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of First Surgery, the Third Affiliated Hospital, NAVY Medical University, Shanghai, People’s Republic of China; 4Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun GuoLiver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Building 19, No. 180, Fenglin Road, Shanghai 20032, People’s Republic of ChinaTel +86-21-54237962Fax +86-21-54237959Email guo.kun@zs-hospital.sh.cnBackground: To date, aberrated lipid metabolism has been recognized as an important feature of hepatocellular carcinoma (HCC); however, it remains poorly defined. As a large member of the low-density lipoprotein receptor family, LRP1B plays a pivotal role in maintaining lipid homeostasis. Here we investigated the expression feature of LRP1B in HCC and elucidated its effects on lipid metabolism of HCC cells.Materials and Methods: LRP1B expression in HCC cells and tumor tissues was respectively examined by quantitative PCR, Western blotting and immunohistochemistry. Crispr-cas9 RNA inference and CRISPRa transcription activation system were used to downregulate and upregulate LRP1B expression, respectively. Oil red O staining, DiD staining combined with flow cytometry and transmission electron microscopy were used to evaluate the lipid content in HCC cells. Overall survival (OS) and time to recurrence (TTR) were calculated; meanwhile, Kaplan–Meier and the Cox proportional hazards model were used to assess the prognosis of HCC patients.Results: In contrast to inactivation expression in a majority of cancers, LRP1B showed predominantly strong expression in HCC. LRP1B knockdown induced the decrease of intracellular lipid content, downregulated expressions of lipid synthesis-related enzymes and upregulated expressions of β-oxidation-related enzymes as well as activated the AMPK signaling. Moreover, HSF1 directly regulated the transcription of LRP1B and was involved in LRP1B-mediated lipid metabolism in HCC; meanwhile, the combination of LRP1B knockdown and HSF1 inhibition suppressed synergistically the proliferation of HCC cells. In addition, simultaneous expression of HSF1 and LRP1B was an independent prognostic factor for HCC patients.Conclusion: Altogether, the study reveals a novel unique role of LRP1B in HCC by serving as a mediator in lipid metabolism, which provides an insight for making explorable therapeutic strategies for HCC.Keywords: hepatocellular carcinoma, lipid metabolism, LRP1B, HSF1, prognosis