Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

Hashemi, Mehrdad; Sabouni, Eisa; Rahmanian, Parham; Entezari, Maliheh; Mojtabavi, Mahsa; Raei, Behnaz; Zandieh, Mohammad Arad; Behroozaghdam, Mitra; Mirzaei, Sepideh; Hushmandi, Kiavash; Nabavi, Noushin; Salimimoghadam, Shokooh; Ren, Jun; Rashidi, Mohsen; Raesi, Rasoul; Taheriazam, Afshin; Αλεξίου, Αθανάσιος; Papadakis, Marios; Tan, Shing Cheng

doi:10.1186/s11658-023-00438-9

Cited by 10 publications

(13 citation statements)

References 284 publications

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“…Overall, these data indicate that curcumin via KLF4 inhibits the expression of Sp1, which in turn is responsible for the downregulation of AATF. Next, we evaluated the levels of activated STAT3, a prominent transcription factor that plays a key role in the progression and metastasis of HCC [38]. As anticipated, the pSTAT3 levels were downregulated in curcumin treated WDSW/CCl 4 mice compared to the vehicle control (Figure 6H).…”

Section: Molecular Mechanism Of Aatf Inhibition By Curcuminmentioning

confidence: 68%

“…Consistent with these studies, we found that in WDSW/CCl 4 mice and AATF control cells, curcumin treatment reduced AATF expression by downregulating Sp1 via KLF4 and thereby exerting anti-tumor activity. It is reported that STAT3 plays a key oncogenic role in cell proliferation, migration, immune suppression, and the angiogenesis of HCC [38]. Studies by Kumar et al, have shown that AATF drives HCC via monocyte chemoattractant protein 1 (MCP1) and STAT3 [21].…”

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confidence: 99%

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AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC

Srinivas

Suresh

Babu

et al. 2023

Preprint

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In tandem with the expanding obesity pandemic, the prevalence of nonalcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic agents to treat the disease. In this study, we aim to examine the hepatoprotective effect of curcumin and elucidate the mechanism by which curcumin ameliorates NASH and prevents tumorigenesis. A preclinical murine model that recapitulates human NASH-HCC in which mice were exposed to a very low dose of carbon tetrachloride (CCl4- 0.2 ul/g) once per week with administration of chow diet and normal water (CDNW) or high-fat western diet and ad lib sugar water (WDSW) was used. Compared to mice on WDSW/CCl4 and vehicle controls, mice receiving WDSW/CCl4 and curcumin showed significant reductions in liver enzymes and dyslipidemia and ameliorated steatosis, lobular inflammation, and hepatocellular ballooning in WDSW/CCl4 mice. In addition, curcumin treatment markedly reduced the hepatic expression of inflammatory markers, fibrogenic genes, and oncogenic markers. Interestingly, curcumin inhibited apoptosis antagonizing transcription factor (AATF), an oncogene overexpressed in NASH-HCC. Furthermore, the anti-tumor effects of curcumin via AATF were validated using human HCC cells. Kruppel-like factor 4 (KLF4) was significantly upregulated by curcumin in NASH liver and HCC cells. Curcumin treatment effectively inhibited the progression of NASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 (specificity protein-1) signaling pathway. Herein, we report the novel molecular link between curcumin and AATF in reducing hepatocarcinogenesis, and these preclinical data provide a strong rationale for developing curcumin for the treatment of NASH-HCC in humans.

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Section: Molecular Mechanism Of Aatf Inhibition By Curcuminmentioning

confidence: 68%

mentioning

confidence: 99%

AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC

Srinivas

Suresh

Babu

et al. 2023

Preprint

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“…Overall, these data indicate that curcumin via KLF4 inhibits the expression of Sp1, which in turn is responsible for the downregulation of AATF. Next, we evaluated the levels of activated STAT3, a prominent transcription factor that plays a key role in the progression and metastasis of HCC (Hashemi et al, 2023). As anticipated, the pSTAT3 levels were downregulated in curcumintreated WDSW/CCl 4 mice compared to the vehicle control (Figure 7a).…”

Section: Molecular Mechanism Of Aatf Inhibition By Curcuminmentioning

confidence: 72%

“…Consistent with these studies, we found that in WDSW/CCl 4 mice and AATF control cells, curcumin treatment reduced AATF expression by downregulating Sp1 via KLF4 and thereby exerting antitumor activity. It is reported that STAT3 plays a key oncogenic role in cell proliferation, migration, immune suppression, and the angiogenesis of HCC (Hashemi et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis antagonizing transcription factor‐mediated liver damage and inflammation to cancer: Therapeutic intervention by curcumin in experimental metabolic dysfunction associated steatohepatitis‐hepatocellular carcinoma

Srinivas,

Suresh,

Chidambaram

et al. 2023

Journal Cellular Physiology

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In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)‐ driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF‐mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH‐HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4‐ 0.2 μL/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel‐like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein‐1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4‐Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH‐HCC in humans.

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“…As the G1 regulatory proteins were regulated by various signaling pathways in which STAT3 has been shown for its roles in hepatocarcinogenesis and progression, 14 , 15 whether pinocembrin affects the STAT3 signaling pathway was then investigated. The phosphorylation of STAT3 at both Tyr705 and Ser727 residues was significantly reduced after the treatment by pinocembrin in both HCC cell lines ( P < .05), as demonstrated in Figure 5A and B .…”

Section: Resultsmentioning

confidence: 99%

Anti-proliferative Effects of Pinocembrin Isolated From Anomianthus dulcis on Hepatocellular Carcinoma Cells

Saengboonmee,

Thithuan,

Mahalapbutr

et al. 2024

Integr Cancer Ther

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Background: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Anomianthus dulcis (Dunal) J.Sinclair (syn. Uvaria dulcis) has been used in Thai traditional medicine in various therapeutic indications. Phytochemical constituents of A. dulcis have been isolated and identified. However, their effects on liver cancer and the associated mechanisms have not been elucidated. Methods: Dry flowers of A. dulcis were extracted using organic solvents, and chromatographic methods were used to purify the secondary metabolites. The chemical structures of the pure compounds were elucidated by analysis of spectroscopic data. Cytotoxicity against HCC cells was examined using SRB assay, and the effects on cell proliferation were determined using flow cytometry. The mechanisms underlying HCC inhibition were examined by molecular docking and verified by Western blot analysis. Results: Among 3 purified flavonoids, pinocembrin, pinostrobin, and chrysin, and 1 indole alkaloid (3-farnesylindole), only pinocembrin showed inhibitory effects on the proliferation of 2 HCC cell lines, HepG2 and Li-7, whereas chrysin showed specific toxicity to HepG2. Pinocembrin was then selected for further study. Flow cytometric analyses revealed that pinocembrin arrested the HCC cell cycle at the G1 phase with a minimal effect on cell death induction. Pinocembrin exerted the suppression of STAT3, as shown by the molecular docking on STAT3 with a better binding affinity than stattic, a known STAT3 inhibitor. Pinocembrin also suppressed STAT3 phosphorylation at both Tyr705 and Ser727. Cell cycle regulatory proteins under the modulation of STAT3, namely cyclin D1, cyclin E, CDK4, and CDK6, are substantially suppressed in their expression levels. Conclusion: Pinocembrin extracted from A. dulcis exerted a significant growth inhibition on HCC cells via suppressing STAT3 signaling pathways and its downstream-regulated genes.

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Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

Cited by 10 publications

References 284 publications

AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC

AATF-mediated Liver Damage and Inflammation to Cancer: Therapeutic Intervention by Curcumin in Experimental MASH-HCC

Apoptosis antagonizing transcription factor‐mediated liver damage and inflammation to cancer: Therapeutic intervention by curcumin in experimental metabolic dysfunction associated steatohepatitis‐hepatocellular carcinoma

Anti-proliferative Effects of Pinocembrin Isolated From Anomianthus dulcis on Hepatocellular Carcinoma Cells

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