Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells

Abstract

Our studies have demonstrated that cell tumorigenicity and pluripotent differentiation potential stem from neural stemness or a neural ground state, which is defined by a regulatory network of higher levels of machineries for basic cell physiological functions, including cell cycle, ribosome biogenesis, protein translation, spliceosome, epigenetic modification factors, reprogramming factors, etc., in addition to the neural stemness specific factors. These machineries and neural stemness factors mostly play cancer-promoting roles. It can be deduced that differentiation requires the repression of neural ground state and causes the reduction or loss of neural ground state and thus tumorigenicity in tumorigenic cells. Formerly, we showed that neuronal differentiation led to reduced tumorigenicity in tumorigenic cells. In the present study, we show that non-neural pro-differentiation factors, such as GATA3, HNF4A, HHEX, and FOXA3 that specify mesodermal or/and endodermal tissues during vertebrate embryogenesis, suppress tumorigenicity via repression of neural stemness and promotion of non-neural property in tumorigenic cells. Mechanistically, these transcription factors repress the transcription of neural enriched genes and meanwhile activate genes that specify non-neural properties via direct binding to the promoters of these genes. We also show that combined expression of HHEX and FOXA3 suppresses tumorigenesis effectively in the AOM/DSS model of colitis-associated cancer. We suggest that targeting the property of neural stemness could be an effective strategy for cancer therapy.

Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential

“…Afterward, cells were permeabilized with 0.1% Triton X-100 for 10 min and blocked with 0.2% fish skin gelatin (Sigma-Aldrich, #G7041) for 30 min at room temperature. Subsequently, primary antibodies were added to cells and incubated Reverse transcriptase-quantitative PCR Total RNA preparation and reverse transcriptasequantitative PCR was performed as described (69). Total RNA was prepared from cells or tumors using TRIzol according to the manufacturer's protocol.…”

Neural Induction: the General Principle for Embryogenesis and Tumorigenesis

“…All pluripotent cells, including cancer cells, NSCs and embryonic pluripotent cells, can be integrated into the development of an embryo and induced to differentiate into normal cells in an embryonic milieu, but form embryoid structures, i.e., tumors, in the absence of correct inducing cues, such as in the process of tumorigenesis or under the skin of an immunodeficient mouse. These studies, together with a recent study (Yang et al, 2021), also suggest that differentiation of cancer cells induced by embryonic inducing factors could be an efficient therapeutic strategy of cancers. The common features of these cells were summarized previously (Cao, 2022).…”

“…Noticeable is that the genes for AKT (AKT1/2/3) and ERK1/2 (MAPK1/3) are all enriched in embryonic neural cells (Magdaleno et al, 2006;Xu et al, 2021), play critical roles in embryonic neural induction and neurodevelopment (Kuroda et al, 2005; Sittewelle and Monsoro-Burq, 2018), and inevitably, promote tumorigenesis. Previous studies generalized that cancer promoting genes are mostly embryonic neural genes, which confer cells with neural stemness, and tumor suppressor genes are mainly non-neural or pro-differentiation genes, which suppress tumorigenicity by inhibiting neural stemness and confer cells with non-neural cell property (Yang et al, 2021;Zhang et al, 2017;Cao, 2017;Cao, 2022). Loss of pro-differentiation or cell specific factors will cause the loss of cell identity and gain of neural stemness and tumorigenicity (Cao, 2022;Xu et al, 2021).…”

The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis

“…Contrary to the conclusion above, the expression of HNF4α in colon cancer leads to the decreased expression of oncogenic factors Lysine Demethylase 1 (ALSD1), SET Domain Containing 1A, Histone Lysine Methyltransferase (SETD1A), Protein Arginine Methyltransferase 1 (PRMT1), FOXM1, Protein Tyrosine Kinase 2 (FAK) and Snail Family Transcriptional Repressor 1(SNAI1), and inhibits the tumor-formation of HCT116 cells ( 35 ).…”