Abstract
Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs’ ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in the world [1]
We recently discovered that shRNA-mediated silencing of the large histone variant macroH2A1 induces similar profound signaling, metabolic and secretomic changes in both cell lines, transforming them in cancer stem cells (CSCs)-like cells, which proliferate
With respect to the transcriptomic changes accompanying the dedifferentiation occurring during the malignant process, here, we employed previously obtained RNA-Seq profiles [17,18,19] and novel data obtained by PCR Open Array analysis, upon macroH2A1 or focal adhesion tyrosine kinase (FAK) KD, respectively
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in the world [1]. HCC contains a population of cancer stem cells (CSCs), which are associated with metastatic potential and disease relapse [2]. Hepatic CSCs are able to self-renew and differentiate to give rise to virtually any HCC cell type [2]. While CSCs themselves do not rapidly proliferate, their progeny have a high proliferative capacity and augment the tumor mass. The gold standard chemotherapeutic agent for HCC patients, increases the median survival time by only a few months [3]. Chemotherapeutic drugs suppress the proliferating cells that comprise the main tumor mass [4], CSCs are very resilient to chemotherapy. It is necessary to develop therapies that target CSCs to enhance patients’ survival and quality of life. Several CSC markers have been identified, including CD133, CD90, CD44, oval cell marker OV6, EpCAM, CD13, CD24, DLK1, α2δ1, ICAM-1, CD47, Lgr, and keratin19 [5], these cells possess a complex cell physiology and pathophysiological role, with considerable crosstalk and redundancy in signaling pathways
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.
