Abstract
Aberrant lipid metabolism is an essential feature of hepatocellular carcinoma (HCC). Fatty acid transport protein-5 (FATP5) is highly expressed in the liver and is involved in the fatty acid transport pathway. However, the potential role of FATP5 in the pathogenesis of HCC remains largely unknown. Herein, we showed that FATP5 was downregulated in HCC tissues and even much lower in vascular tumor thrombi. Low expression of FATP5 was correlated with multiple aggressive and invasive clinicopathological characteristics and contributed to tumor metastasis and a poor prognosis in HCC patients. FATP5 inhibited the epithelial–mesenchymal transition (EMT) process and suppressed HCC cell migration and invasion, while silencing FATP5 had the opposite effects. Mechanistically, knockdown of FATP5 promoted cellular glycolytic flux and ATP production, thus suppressing AMP-activated protein kinase (AMPK) and activating its downstream signaling mammalian target of rapamycin (mTOR) to support HCC progression and metastasis. Activation of AMPK using metformin reversed the EMT program and impaired the metastatic capacity of FATP5-depleted HCC cells. Collectively, FATP5 served as a novel suppressor of HCC progression and metastasis partly by regulating the AMPK/mTOR pathway in HCC, and targeting the FATP5-AMPK axis may be a promising therapeutic strategy for personalized HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer globally and results in significant health-related problems, making it the third leading cause of cancer-related deaths [1]
In addition to the widely accepted aerobic glycolysis, exacerbated de novo lipogenesis has been proposed as an emerging metabolic hallmark of HCC that is critical for cancer cell growth and survival under stressful conditions [8, 24]
The aforementioned observations suggested the inhibitory role of fatty acid (FA) transport in HCC development, yet the underlying mechanisms involved in this metabolic phenotype remain elusive
Summary
Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer globally and results in significant health-related problems, making it the third leading cause of cancer-related deaths [1]. Early HCC can be cured by liver resection in selected candidates, most patients are still diagnosed at advanced stages for which potentially curative therapies are no longer considered [2]. Even for patients who have undergone curative resection for resectable or localized HCCs, the longterm outcomes remain dismal primarily because of the high incidences of tumor metastasis, with up to 70% of cases developing recurrence within 5 years after surgery [3]. Multiple molecular targets and signaling pathways have been investigated in HCC, the definitive mechanisms underlying HCC development and progression remain elusive; effective antitumor agents have not been developed. Alterations in fatty acid (FA) metabolism have been increasingly recognized in multiple malignancies, including HCC [5]. Fatty acid transport is a general metabolic pathway and plays pivotal roles in hepatocarcinogenesis [9]. The results from Doege et al, using a FATP5-knockout mouse model, revealed that silencing FATP5 in vivo significantly improved whole-body insulin
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
