GCF2 mediates nicotine-induced cancer stemness and progression in hepatocellular carcinoma.

Cigarette smoking is one of the most impactful behavior-related risk factors for multiple cancers including hepatocellular carcinoma (HCC). Nicotine, as the principal component of tobacco, is not only responsible for smoking addiction but also a carcinogen; nevertheless, the underlying mechanisms remain unclear. Here we report that nicotine enhances HCC cancer stemness and malignant progression by upregulating the expression of GC-rich binding factor 2 (GCF2), a gene that was revealed to be upregulated in HCC and whose upregulation predicts poor prognosis, and subsequently activating the Wnt/ꞵ-catenin/SOX2 signaling pathway. We found that nicotine significantly increased GCF2 expression and that silencing of GCF2 reduced nicotine-induced cancer stemness and progression. Mechanistically, nicotine could stabilize the protein level of GCF2, and then GCF2 could robustly activate its downstream Wnt/ß-catenin signaling pathway. Taken together, our results thus suggest that GCF2 is a potential target for a therapeutic strategy against nicotine-promoted HCC.

Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases.

Leucine Rich Repeat of Flightless-1 Interacting Protein 1/GC-binding factor 2 (LRRFIP1/GCF2) cDNA was cloned for a transcriptional repressor GCF2, which bound sequence-specifically to a GC-rich element of epidermal growth factor receptor (EGFR) gene and repressed its promotor. LRRFIP1/GCF2 was also cloned as a double stranded RNA (dsRNA)-binding protein to trans-activation responsive region (TAR) RNA of Human Immunodeficiency Virus-1 (HIV-1), termed as TAR RNA interacting protein (TRIP), and as a binding protein to the Leucine Rich Repeat (LRR) of Flightless-1(Fli-1), termed as Flightless-1 LRR associated protein 1 (FLAP1) and LRR domain of Flightless-1 interacting Protein 1 (LRRFIP1). Subsequent functional studies have revealed that LRRFIP1/GCF2 played multiple roles in the regulation of diverse biological systems and processes, such as in immune response to microorganisms and auto-immunity, remodeling of cytoskeletal system, signal transduction pathways, and transcriptional regulations of genes. Dysregulations of LRRFIP1/GCF2 have been implicated in the causes of several experimental and clinico-pathological states and the responses to them, such as autoimmune diseases, excitotoxicity after stroke, thrombosis formation, inflammation and obesity, the wound healing process, and in cancers. LRRFIP1/GCF2 is a bioregulator in multidisciplinary systems of the human body and its dysregulation can cause diverse human diseases.