Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g., by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.

https://www.mdpi.com/2072-6694/11/9/1280/pdf

STAT3, a Master Regulator of Anti-Tumor Immune Response.

Role of CD8+ T lymphocyte cells: Interplay with stromal cells in tumor microenvironment

Gallic acid for cancer therapy: Molecular mechanisms and boosting efficacy by nanoscopical delivery.

Abstract Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, tumor inflammation, metabolism reprogramming, drug resistance, cancer stemness. Therefore, STAT3 has become a promising therapeutic target in a wide range of cancers. This review focuses on the up-to-date knowledge of STAT3 signaling in cancer. We summarize both the positive and negative modulators of STAT3 together with the cancer hallmarks involving activities regulated by STAT3 and highlight its extremely sophisticated regulation on immunosuppression in tumor microenvironment and metabolic reprogramming. Direct and indirect inhibitors of STAT3 in preclinical and clinical studies also have been summarized and discussed. Additionally, we highlight and propose new strategies of targeting STAT3 and STAT3-based combinations with established chemotherapy, targeted therapy, immunotherapy and combination therapy. These efforts may provide new perspectives for STAT3-based target therapy in cancer. 

Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery

Primary liver cancer (PLC) is one of the most common solid malignancies. However, PLC drug development has been slow, and first-line treatments are still needed; thus, studies exploring and developing alternative strategies for effective PLC treatment are urgently needed. Chinese herbal medicine (CHM) has long been applied in the clinic due to its advantages of low toxicity and targeting of multiple factors and pathways, and it has great potential for the development of novel natural drugs against PLC. Purpose: This review aims to provide an update on the pharmacological mechanisms of Chinese patent medicines (CPMs) and the latest CHM-derived compounds for the treatment of PLC and relevant clinical evaluations. Materials and Methods: A systematic search of English literature databases, Chinese literature, the Clinical Trials Registry Platform, and the Chinese Clinical Trial Registry for studies of CHMs for PLC treatment was performed. Results: In this review, we summarize the clinical trials and mechanisms of CPMs for PLC treatment that have entered the clinic with the approval of the Chinese medicine regulatory authority. These CPMs included Huaier granules, Ganfule granules, Fufang Banmao capsules, Jinlong capsules, Brucea javanica oil emulsions, and compound kushen injections. We also summarize the latest in vivo, in vitro, and clinical studies of CHM-derived compounds against PLC: icaritin and ginsenoside Rg3. Dilemmas facing the development of CHMs, such as drug toxicity and low oral availability, and future developments are also discussed. Conclusion: This review provides a deeper the understanding of CHMs as PLC treatments and provides ideas for the development of new natural drugs against PLC.

/pdf/chinese-herbal-medicine-for-primary-liver-cancer-therapy-66tusoqe.pdf

Chinese Herbal Medicine for Primary Liver Cancer Therapy: Perspectives and Challenges

Resveratrol is a common, naturally occurring polyphenol confirmed with inhibited the cellular effects of carcinogenesis. However, the molecular mechanism underlying resveratrol's action against hepatocellular carcinoma (HCC) is still unclear. In addition, MARCH1 promotes the initiation and progression of HCC, but it is unclear whether resveratrol exerts antitumor efforts by regulating MARCH1 expression. This study determined the molecular mechanisms underlying the antitumor effects of resveratrol in HCC. Resveratrol induced apoptosis and inhibited the proliferation, migration, and invasion of HCC cell lines (HepG2 and Hep3B). In addition, it inhibited MARCH1 and phospho-protein kinase B (p-AKT) expression but upregulated the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) dose-dependently both in vitro and in vivo. MARCH1 knockdown by small interfering RNA (siRNA) also increased PTEN expression. Meanwhile, MK2206 (an AKT inhibitor) and bisperoxovanadium (BPV; a PTEN inhibitor) combined with resveratrol decreased MARCH1 expression more than the single-treatment HCC group. These results suggested that resveratrol affects the biological characteristics of HCC via downregulation of MARCH1 expression.

Resveratrol inhibits the malignant progression of hepatocellular carcinoma via MARCH1-induced regulation of PTEN/AKT signaling.

Hepatocellular carcinoma (HCC) is one of the most common cancer types worldwide. The signal transducer and activator of transcription 3 (STAT3) protein is a member of the STAT transcription factor family. Oncogenesis, invasion, and metastasis of HCC are associated with activation of STAT3. However, whether aberrant expression of phosphorylated STAT3 (p-STAT3) in peripheral CD4+ and CD8+ T cells relates to HCC pathogenesis remains unclear. In this study, the expression of p-STAT3 in CD4+ and CD8+ T cells, and the levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-6 and IL-10 in the human hepatoma cell line Huh7 co-cultured with peripheral blood mononucleated cells (PBMCs) of healthy volunteers were measured. The correlations between p-STAT3 and IFN-γ/IL-4, IFN-γ, IL-4, IL-6 and IL-10 were then analyzed. Results showed that the p-STAT3 level is higher in CD4+ and CD8+ T cells in the peripheral blood of HCC patients, and in PBMCs co-cultured with Huh7 cells compared to controls. The cytokine (IL-4, IL-6 and IL-10) levels were increased and the IFN-γ level was decreased in the serum of HCC patients and in supernatants of PBMCs co-cultured with Huh7 cells. Correlation analyses demonstrated that the IFN-γ/IL-4 ratio and the IFN-γ level negatively correlate to the p-STAT3 level in CD4+ and CD8+ T cells in samples from patients and in cells cultured in vitro. By contrast, the levels of IL-4, IL-6 and IL-10 positively correlated to the p-STAT3 level. This study indicated that the expression of p-STAT3 is upregulated in peripheral CD4+ and CD8+ T cells of HCC patients, and which may result in abnormal immune surveillance and thereby, contribute to HCC pathogenesis.

/pdf/aberrant-expression-of-p-stat3-in-peripheral-blood-cd4-and-1p6ung6ngf.pdf

Aberrant expression of p-STAT3 in peripheral blood CD4+ and CD8+ T cells related to hepatocellular carcinoma development.

Myricetin is a type of natural flavonol known for its anticancer activity. However, the molecular mechanism of myricetin in anti-hepatocellular carcinoma (HCC) is not well defined. Previous studies indicated that downregulation of membrane-associated RING-CH finger protein 1 (MARCH1) contributed to the treatment of a variety of cancers. Whether the anticancer property of myricetin is associated with MARCH1 expression remains to be investigated. This research explored the anti-HCC mechanism of myricetin. Our results indicate that myricetin induces autophagy and arrests cell cycle at the G2/M phase to suppress the proliferation of HCC cells by downregulating MARCH1. Myricetin reduces MARCH1 protein in Hep3B and HepG2 cells. Interestingly, myricetin upregulates the MARCH1 mRNA level in Hep3B cells but downregulates it in HepG2 cells. The knockdown of MARCH1 by siRNAs (small interfering RNAs) decreases the phosphorylated p38 MAPK (p-p38 MAPK) and Stat3 (p-Stat3), and inhibits HCC cell viability. Moreover, myricetin inhibits p38 MAPK and Stat3 signaling pathways by downregulating MARCH1 to repress HCC growth both in vitro and in vivo. Bafilomycin A1 (BafA1), an autophagy inhibitor, has synergetic effect with myricetin to inhibit HCC growth. Taken together, our results reveal that myricetin inhibits the proliferation of HCC cells by inhibiting MARCH1-regulated p38 MAPK and Stat3 signaling pathways. This research provides a new molecular mechanism for myricetin in anti-HCC and suggests that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.

/pdf/myricetin-induces-autophagy-and-cell-cycle-arrest-of-hcc-by-275aktivnc.pdf

Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways

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Resveratrol inhibits the malignant progression of hepatocellular carcinoma via MARCH1-induced regulation of PTEN/AKT signaling.

Aberrant expression of p-STAT3 in peripheral blood CD4+ and CD8+ T cells related to hepatocellular carcinoma development.

Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways