Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

/pdf/hepatic-stellate-cells-and-hepatocarcinogenesis-2ywbn6yu6g.pdf

Hepatic Stellate Cells and Hepatocarcinogenesis

OBJECTIVE Phosphatase and tensin homologue deleted on chromosome ten (PTEN) regulates cell proliferation and apoptosis by inhibiting phosphatidylinositol-3 kinase (PI3K) and protein kinase (AKT) signaling. High expression of miR-21 was associated with ovarian cancer. This study aims to investigate whether miR-21 regulates PTEN/PI3K/AKT signaling as well as its role in the proliferation and apoptosis of ovarian cancer cells. MATERIALS AND METHODS Bioinformatics analysis was used to identify the binding site between miR-21 and the 3'-UTR of PTEN mRNA. A dual-luciferase reporter gene assay was performed to confirm the relationship between miR-21 and PTEN. The expression of miR-21, PTEN, and p-AKT was measured in normal ovarian cell IOSE80, ovarian cancer cell lines A2780, and SKOV3. miR-NC or miR-21 inhibitor was transfected into A2780 or SKOV3 cells followed by the analysis of the expression of miR-21, PTEN, p-AKT, cell apoptosis by flow cytometry, and proliferation by EdU assay. RESULTS There was a targeted relationship between miR-21 and PTEN. Compared with IOSE80 cell, levels of miR-21 and p-AKT were significantly elevated in A2780 and SKOV3 cells, with the statistical reduction of PTEN expression (p<0.05). The inhibition of miR-21 significantly reduced the expressions of miR-21 and p-AKT and induced PTEN level in A2780 and SKOV3 cells, which also restricted cell proliferation and promoted cell apoptosis. CONCLUSIONS The miR-21 expression is found elevated in ovarian cancer cells. The suppression of miR-21 increases PTEN expression, inhibits PI3K/AKT activity, promotes cell apoptosis, and reduces cell proliferation. This finding provides new leads to the future treatment of ovarian cancer.

miR-21 regulates the proliferation and apoptosis of ovarian cancer cells through PTEN/PI3K/AKT.

Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial–mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.

Targeting CTGF in Cancer: An Emerging Therapeutic Opportunity

Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer.

MicroRNA-212-3p inhibits several human cancers but its effects on hepatocellular carcinoma (HCC) remain unclear. In this study, we show that miR-212-3p is down-regulated in HCC cell lines and tissues, and correlates with vascular invasion (p = 0.001), and the absence of capsule formation (p = 0.009). We found that miR-212-3p influenced the epithelial to mesenchymal transition (EMT) of HCCLM3 and Huh7 cells. Mechanistically, miR-212-3p repressed cell invasion through the suppression of connective tissue growth factor (CTGF). We therefore validate the anti-HCC effects of miR-212-3p through its ability to suppress CTGF and subsequent EMT.

/pdf/microrna-212-3p-inhibits-the-proliferation-and-invasion-of-3maag9xc3y.pdf

MicroRNA-212-3p inhibits the Proliferation and Invasion of Human Hepatocellular Carcinoma Cells by Suppressing CTGF expression.

Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.

/pdf/mir-494-3p-promotes-pi3k-akt-pathway-hyperactivation-and-179w6pqmq8.pdf

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN.

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MicroRNA-212-3p inhibits the Proliferation and Invasion of Human Hepatocellular Carcinoma Cells by Suppressing CTGF expression.

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN.