Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent malignancies, worse still, there are very limited therapeutic measures with poor clinical outcomes. Dietary restriction (DR) has been known to inhibit spontaneous and induced tumors in several species, but the mechanisms are little known. In the current study, by using a diethylnitrosamine (DEN)-induced HCC mice model, we found that DR significantly reduced the hepatic tumor number and size, delayed tumor development, suppressed proliferation and promoted apoptosis. Further transcriptome sequencing of liver tissues from the DEN and the DEN accompanied with DR (DEN+DR) mice showed that DEN induced profound changes in the gene expression profile, especially in cancer-related pathways while DR treatment reversed most of the disturbed gene expression induced by DEN. Finally, transcription factor enrichment analysis uncovered the transcription factor specificity protein 1 (SP1) probably functioned as the main regulator of gene changes, orchestrating the protective effects of DR on DEN induced HCC. Taken together, by the first comprehensive transcriptome analysis, we elucidate that DR protects aginst DEN-induced HCC by restoring the disturbed gene expression profile, which holds the promise to provide effective molecular targets for cancer therapies.

Effects of Dietary Restriction on Cancer Development and Progression

“…Liver cells of diethylnitrosamine (DEN)-induced HCC mice models submitted to DR showed a reduction in levels of NF-kB, a mediator of inflammation associated with cell proliferation and cancer (Duan et al 2017). A decrease in levels of cytokines and inflammatory chemokines was observed in murine liver, kidney, and spleen tissues (Chiba and Ezaki 2010).…”

“…3 Correlation between calorie intake and adiposity. Excessive calorie intake causes hyperinsulinemia, hypertrophy of adipose tissue, and increased inflammation DEN-induced mice HCC cells exhibit high levels of Caspasi 3, PARP, and Citocromo C, which are proteins involved in mitochondria-mediated autophagy, suggesting that DR suppresses proliferation and promotes apoptosis (Lu et al 2008;Duan et al 2017).…”

“…The benefits are due to the negative regulation of nutrient-signaling pathways, including insulin-like growth factor 1 (IGF-1) pathway and its effector extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K), which are known to modulate important proliferation pathways (Cangemi et al 2016). Furthermore, it is well known that genomic instability is a distinctive feature of cancer, and CR tumor response seems to play a key role for the maintenance of genomic integrity (Robertson and Mitchell 2013;Duan et al 2017). Due to these evidences, new metabolic approaches are being sought today for anticancer treatment.…”

“…MAPK pathway regulated by RAS promotes tumor growth and is one of the most important molecular targets for treatment of several types of cancers (Duan et al 2017). …”

Effects of Dietary Restriction on Cancer Development and Progression

“…Several studies showed that DR also plays a role in modulating inflammatory response. Liver cells of diethylnitrosamine (DEN)-induced HCC mice models submitted to DR showed a reduction in levels of NF-kB, a mediator of inflammation associated with cell proliferation and cancer (Duan et al 2017). A decrease in levels of cytokines and inflammatory chemokines was observed in murine liver, kidney, and spleen tissues (Chiba and Ezaki 2010).…”