Silymarin‑mediated regulation of the cell cycle and DNA damage response exerts antitumor activity in human hepatocellular carcinoma

Abstract

A novel module-search algorithm method was used to screen for potential signatures and investigate the molecular mechanisms of inhibiting hepatocellular carcinoma (HCC) growth following treatment with silymarin (SM). The modules algorithm was used to identify the modules via three major steps: i) Seed gene selection; ii) module search by seed expansion and entropy minimization; and iii) module refinement. The statistical significance of modules was computed to select the differential modules (DMs), followed by the identification of core modules using the attract method. Pathway analysis for core modules was implemented to identify the biological functions associated with the disease. Subsequently, results were verified in an independent sample set using reverse transcription polymerase chain reaction (RT-PCR). In total, 18 seed genes and 12 DMs (modules 1–12) were identified. The core modules were isolated using gene expression data. Overall, there were 4 core modules (modules 11, 5, 6 and 12). Additionally, DNA topoisomerase 2-binding protein 1 (TOPBP1), non-structural maintenance of chromosomes condensing I complex subunit H, nucleolar and spindle associated protein 1 (NUSAP1) and cell division cycle associated 3 (CDCA3) were the initial seed genes of module 11, 5, 6 and 12, respectively. Pathway results revealed that cell cycle signaling pathway was enriched by all core modules simultaneously. RT-PCR results indicated that the level of CDCA3, TOPBP1 and NUSAP1 in SM-treated HCC samples was markedly decreased compared with that in non-SM-treated HCC. No statistically significant difference between the transcriptional levels of CDCA3 in SM-treated and non-treated HCC groups was identified, although CDCA3 expression was increased in the treated group compared with the untreated group. Furthermore, although the expression level of TOPBP1 and NUSAP1 in the SM-treated group was decreased compared with that in the normal group, no significant difference was observed. From the results of the present study it can be inferred that TOPBP1, NUSAP1 and CDCA3 of the core modules may serve notable functions in SM-associated growth suppression of HCC.

The protective mechanism of Nigella sativa against diethylnitrosamine‐induced hepatocellular carcinoma through its antioxidant effect and EGFR/ERK1/2 signaling

“…17 Recently, it was found that it has an antitumor activity in HCC. 18 To the extent of our knowledge, no studies investigated the effect of NSEE, TQ, or silymarin on EGFR/ERK1/2 signaling pathway in DENA-induced HCC in rats. Consequently, we designed our study to focus on the chemopreventive effect of NSEE, TQ, or silymarin as a hepatoprotective agent on the EGFR/ERK1/2 signaling in the precancerous stage of HCC in rats induced by DENA and CCl 4 .…”

“…Silymarin is nontoxic to humans and has been employed as a protective treatment in acute and chronic liver diseases . Recently, it was found that it has an antitumor activity in HCC . To the extent of our knowledge, no studies investigated the effect of NSEE, TQ, or silymarin on EGFR/ERK1/2 signaling pathway in DENA‐induced HCC in rats.…”

Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression

“…This discovery contributes to the evolving understanding of NUSAP1's role as a pivotal mediator of CAF activation, linking extracellular cues like lactate to intracellular signaling pathways. This may also elucidate the multifaceted functions of NUSAP1 in cellular processes beyond mitosis [ 70 , 71 ]. Importantly, the upregulation of DESMIN-positive CAFs, induced by lactate treatment and NUSAP1-mediated mechanisms, reveals intriguing functional consequences.…”

Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View

“…Looking towards bioactive compounds derived from plants that target IL-6 in HCC, including Curcuma phaeocaulis [135], Curcuma aromatica, Polygonum cuspidatum [136], and Silybum marianum [137], it has been shown that curcumin inhibits IL-6-induced JAK/STAT3 signaling cascades through negative feedback, suppressing the development of inflammation in HCC [135]. Even though their molecular mechanism is not fully understood, both silymarin and resveratrol are also used as alternative treatments for their anti-HCCassociated effects, possibly through the induction of cell cycle arrest [137] and the installation of apoptotic cell death [136].…”