Non-coding RNAs-regulated SLC7A11 modulates ferroptosis: a new strategy for cancer therapy.

Liver cancer has a high incidence and mortality rate worldwide, and there is an urgent need to identify new therapeutic strategies and predictive targets to improve the clinical outcomes of advanced liver cancer. Ferroptosis holds promise as a novel strategy for cancer therapy. Epigenetic dysregulation is a hallmark of cancer, and noncoding RNAs are tightly involved in cell fate determination. Therefore, we aimed to identify a novel ferroptosis regulator from aberrantly expressed microRNAs that may serve as a novel biomarker and therapeutic target for liver cancer. The expression signature and prognostic value of miR-339 was assessed using TCGA data set. The role of miR-339/ATG7/FTH1 axis in liver cancer cells were evaluated through growth curve, colony formation, 7-AAD staining. The role of miR-339 in regulation of ferroptosis was determined by immunofluorescence staining, flow cytometry, and Elisa kits. Here, we showed that miR-339 is aberrantly overexpressed in patients with liver cancer. In addition, miR-339 inhibition dramatically suppresses liver cancer progression. Furthermore, miR-339 silencing drives cell death and inhibits liver cancer progression, indicating that miR-339 may serve as a novel ferroptosis suppressor. Mechanistically, we demonstrated that miR-339 targets ATG7 to facilitate the autophagic degradation of FTH1 and prevent ferroptosis in liver cancer cells. We provide important evidence that the miR-339 inhibition activates of the autophagy pathway to promote ferroptosis by degrading FTH1 in liver cancer cells. We found that miR-339 regulates the balance between ferroptosis and autophagy in liver cancer cells.

Accumulating lines of evidence have revealed that microRNAs (miRNAs) play critical roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation. They act either as tumour suppressors or oncogenes, and alteration in their expression patterns has been linked to onset, progression and chemoresistance of various cancers. Moreover, miRNAs are also crucial for the regulation of cancer stem cells (CSCs) self-renewal and proliferation as well as control of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. Therefore, exploitation of miRNAs as targets for cancer prevention and therapy could be a promising approach. Several experimental and epidemiologic studies have shown that dietary intake of natural agents such as baicalin, ginsenoside, curcumin, resveratrol, genistein, epigallocatechin-3-gallate (EGCG), indole-3-carbinol, 3,3΄-diindolylmethane (DIM) including antioxidants among others is inversely associated with the risk for cancer, demonstrating the inhibitory effects of natural agents on carcinogenesis. Moreover, the anticancer agents from natural plants have been found to inhibit the development and progression of cancer through the regulation of cellular signaling pathways. Importantly, natural agents also up-regulate the expression of tumor-suppressive miRNAs and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of cancer cell growth and cancer stem cell self-renewal through modulation of cellular signaling network. Furthermore, natural agents also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in cancer cells. Therefore, natural agents could have much broader use in the prevention and/or treatment of various types of cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of natural agents in the prevention and/or treatment of cancer. Herein, we provide an overview of natural agents’ modulation of miRNA expression as well as highlight the significance of these observations as potential new strategies in cancer therapies. This review will help us to know in detail how miRNAs are regulated by natural agents and also help to develop more effective and secure natural agents for clinical therapies.

Dynamic and Temporal Transcriptomic Analysis Reveals Ferroptosis-Mediated Antileukemia Activity of S-Dimethylarsino-Glutathione: Insights into Novel Therapeutic Strategy

Ferroptosis is an iron-dependent nonapoptotic kind of regulated cell death resulting from the destruction of redox balance in the cytosol. Unlike apoptosis, ferroptosis is caused by an increase in intracellular iron and lipid peroxides that causes significant damage to the membrane lipid bilayer and mitochondria leading to cell death. Increased iron level in the cell promotes ROS production. Ferroptosis inducer molecules increase ROS production and inhibit the antioxidant defence mechanism to facilitate ferroptosis in cancer cells. Inhibition of GPX4, redox-active iron availability, and lipid peroxidation are major contributors to ferroptosis. Ferroptosis is involved in many diseases like heart disease, neurodegenerative disease, and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. In this review, we discuss the regulatory mechanism of ferroptosis, its different hallmarks, including genetic and metabolic regulators and inducers that promote ferroptosis in the cancer cells. Finally, the latest progress and development in ferroptosis research in different cancers focusing on proposing a novel strategy in cancer therapy are discussed.

Non-coding ribonucleic acids were thought to be non-functional transcription products decades ago. But recently they have been found to play an essential role in programmed regulation in a variety of diseases, including cancer. They include micro ribonucleic acids and their upstream long non-coding ribonucleic acids and circular ribonucleic acids. Long non-coding ribonucleic acids or circular ribonucleic acids can form a regulatory network through sponging micro ribonucleic acids. The network regulates biological functions of various tumors such as proliferation, invasion and drug resistance. In addition, other non-coding ribonucleic acids such as piwi-interacting ribonucleic acids, transfer ribonucleic acids, ribosomal ribonucleic acids, small nuclear ribonucleic acids and small nucleolar ribonucleic acids can also act as regulators of the biological characteristics of tumor cells. Ferroptosis is a programmed cell death, which is distinct from the classical caspase splicing and has received increasing attention in recent years with regard to the tumorigenesis and treatment of cancer. Interestingly, non-coding ribonucleic acids have been found to regulate ferroptosis in tumors and to maintain the biological function of tumor cells. Herein, we summarize the related research and emphasize that the regulation of ferroptosis in tumor cells by non-coding ribonucleic acids may provide a basis for future targeted cancer therapy.

Ferroptosis has been implicated in pulmonary hypertension (PH), and chromatin-associated RNAs are increasingly recognized as key regulators of this process. However, the detailed mechanism remains unexplored. Bioinformatics, Sanger sequencing, and RNase R digestion were used to identify the upregulation of ca-circSCN8A. Functional gain and loss assays were used to unveil the role of ca-circSCN8A in hypoxic redox-dependent ferroptosis in human pulmonary arterial smooth muscle cells and a PH mice model. Interaction between ca-circSCN8A and FUS was detected via RNA immunoprecipitation and pull-down assays. Fluorescence recovery after photobleaching, ChIRP-qPCR (Chromatin Isolation by RNA Purification followed by Quatitative PCR), malondialdehyde, reduced glutathione, and glutathione were conducted to explore the potential molecular mechanism. ca-circSCN8A was identified and confirmed to be upregulated in PH. Its overexpression promoted hypoxia-induced ferroptosis in human pulmonary arterial smooth muscle cells. Under hypoxic conditions, ca-circSCN8A recruited EP300 to facilitate the lactylation of FUS (Fused in Sarcoma), triggering the formation of a ca-circSCN8A/FUS/EP300 complex via liquid-liquid phase separation. Liquid-liquid phase separation maintained the stability of the R-loop formed by ca-circSCN8A and ferroptosis-related gene SLC7A11 (solute carrier family 7 member 11) promoter that inhibits its transcription, further result in the disruption of the redox homeostasis and causing ferroptosis in human pulmonary arterial smooth muscle cells. ca-circSCN8A recruits EP300 to promote the lactylation of FUS, thereby driving liquid-liquid phase separation-mediated complex formation with FUS and EP300. This process enables ca-circSCN8A to form an R-loop with the nonhost SLC7A11 promoter, contributing to the regulation of hypoxia-induced ferroptosis in human pulmonary arterial smooth muscle cells. This study provides the first evidence that circRNAs can form R-loops with nonhost genes in a liquid-liquid phase separation-dependent manner. Our findings highlight ca-circSCN8A as a crucial regulator of ferroptosis in hypoxic PH and a potential therapeutic target for PH.

MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3′-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer patients.

Targeting tumor highly-expressed LAT1 transporter with amino acid-modified nanoparticles: Toward a novel active targeting strategy in breast cancer therapy

pH-Sensitive nano-systems for drug delivery in cancer therapy

PVT1, a long non-coding RNA has been implicated in a variety of human cancers. Recent advancements have led to increasing discovery of the critical roles of PVT1 in cancer initiation and progression. Novel insight is emerging about PVT1's mechanism of action in different cancers. Identifying and understanding the variety of activities of PVT1 involved in cancers is a necessity for the development of PVT1 as a diagnostic biomarker or therapeutic target in cancers where PVT1 is dysregulated. PVT1's varied activities include overexpression, modulation of miRNA expression, protein interactions, targeting of regulatory genes, formation of fusion genes, functioning as a competing endogenous RNA (ceRNA), and interactions with MYC, among many others. Furthermore, bioinformatic analysis of PVT1 interactions in cancers has aided understanding of the numerous pathways involved in PVT1 contribution to carcinogenesis in a cancer type—specific manner. However, these recent findings show that there is much more to be learned to be able to fully exploit PVT1 for cancer prognostication and therapy. In this review, we summarize some of the latest findings on PVT1's oncogenic activities, signaling networks and how targeting these networks can be a strategy for cancer therapy.

Ferroptosis is a distinct form of programmed cell death that differs from other pathways. It is characterized by iron-dependent lipid peroxidation and results in morphologically lethal cellular damage. With advancing insight, triggering ferroptosis is a promising strategy for cancer therapy. RNA-binding proteins (RBPs) comprise a diverse group of molecules that regulate various RNA processes through interactions with transcripts. Research has highlighted the pivotal role of RBPs in controlling biological functions. Evidence indicates that RBPs play important roles in regulating ferroptosis. Heterogeneous nuclear ribonucleoprotein U (HnRNPU) is a well-known RBP involved in RNA splicing, messenger RNA stability and chromatin organization. Elevated HnRNPU expression has been implicated in cancer progression and is associated with poor prognosis. However, the function and underlying mechanisms of HnRNPU in colon adenocarcinoma (COAD) remain poorly understood. Here we identify increased HnRNPU expression in patients with COAD, with higher levels correlating with poor patient survival. HnRNPU knockdown inhibited cell proliferation and induced cell cycle arrest by suppressing cyclin E1 and CDK2. RNA-sequencing analysis revealed HnRNPU’s involvement in ferroptosis regulation. In line with this, HnRNPU deletion induced ferroptosis and increased sensitivity to RSL3 treatment and cysteine deprivation. xCT overexpression (SLC3A2/SLC7A11) counteracted the antiproliferative and proferroptotic effects of HnRNPU knockdown. Mechanistically, HnRNPU stabilized the mRNAs of SLC7A11 and SLC3A2 by binding to their 3′ untranslated regions, thereby promoting cysteine uptake and glutathione synthesis. Findings demonstrate that HnRNPU promotes proliferation and inhibits ferroptosis by regulating the mRNA stability of SLC7A11 and SLC3A2. Targeting HnRNPU is a potential therapeutic approach for COAD treatment.

Rationale: Cancer continues to be a significant public health issue. Traditional treatments such as surgery, radiotherapy, and chemotherapy often fall short because of intrinsic issues such as lack of specificity and poor drug delivery, leading to insufficient drug concentration at the tumor site and/or potential side effects. Consequently, improving the delivery of conventional chemotherapy drugs like doxorubicin (DOX) is crucial for their therapeutic efficacy. Successful cancer treatment is achieved when regulated cell death (RCD) of cancer cells, which includes apoptotic and non-apoptotic processes such as ferroptosis, is fundamental to successful cancer treatment. The developing field of nanozymes holds considerable promise for innovative cancer treatment approaches. Methods: A dual-metallic nanozyme system encapsulated with DOX was created, derived from metal-organic frameworks (MOFs), designed to combat tumors by depleting glutathione (GSH) and concurrently liberating DOX. The initial phase of the study examined the GSH oxidase-mimicking function of the dimetallic nanozyme (ZIF-8/SrSe) through enzyme kinetic assays and Density Functional Theory (DFT) simulations. Following this, we probed the ability of ZIF-8/SrSe@DOX to release DOX in response to the tumor microenvironment in vitro, alongside examining its anticancer capabilities and mechanisms prompting apoptosis or ferroptosis in cancer cells. Moreover, we established tumor-bearing animal models to corroborate the anti-tumor effectiveness of our nanozyme complex and to identify the involved apoptotic and ferroptotic pathways implicated. Results: Enzyme kinetic analyses demonstrated that the ZIF-8/SrSe nanozyme exhibits substantial GSH oxidase-like activity, effectively oxidizing reduced GSH to glutathione disulfide (GSSG), while also inhibiting glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). This inhibition led to an imbalance in iron homeostasis, pronounced caspase activation, and subsequent induction of apoptosis and ferroptosis in tumor cells. Additionally, the ZIF-8/SrSe@DOX nanoparticles efficiently delivered DOX, causing DNA damage and further promoting apoptotic and ferroptotic pathways. Conclusions: This research outlines the design of a novel platform that combines chemotherapeutic agents with a Fenton reaction catalyst, offering a promising strategy for cancer therapy that leverages the synergistic effects of apoptosis and ferroptosis.

After an initial positive response to chemotherapy, cancer patients often acquire chemoresistance and tumor relapse, which makes cancer one of the most lethal diseases worldwide. Exosomes are essential mediators of cell-to-cell communication by delivering their cargo, such as proteins, RNAs and DNA, from cell to cell. They participate in cancer progression, metastasis, immune response and therapy resistance. Their ability to shuttle between cells makes them efficient drug delivery systems. As drug transporters, they provide novel strategies for cancer therapy by advancing targeted drug therapy and improving the therapeutic effects of anti-cancer medications. In this review, a comprehensive overview of the potential of exosomes as therapeutic agents and targeted molecules in the treatment of cancer patients is given. The current challenges of preparation of exosomes loaded with drugs and delivering them to the recipient tumor cells as well as a consequent exosome-mediated cancer therapy are also discussed.

After an initial positive response to chemotherapy, cancer patients often acquire chemoresistance and tumor relapse which make cancer to the most lethal diseases worldwide. Exosomes are essential mediators of cell-to-cell communication by delivering their cargo, such as proteins, RNAs and DNA from cell to cell. They participate in cancer progression, metastasis, immune response and therapy resistance. Their ability to shuttle between cells make them to efficient drug delivery systems. As drug transporters, they provide novel strategies for cancer therapy by advancing targeted drug therapy and improving the therapeutic effects of anti-cancer medications. With this review, a comprehensive overview on the potential of exosomes as therapeutics agents and targeted molecules in the treatment of cancer patients is given. The current challenges of preparation of loading exosomes with drugs and delivering them to the recipient tumor cells as well as a consequent exosome-mediated cancer therapy are also discussed.

Human cancers often exhibit increased microRNA (miRNA) biogenesis and global aberrant expression of miRNAs; thus, targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-203 enhances the biogenesis of tumor suppressor let-7 in lung cancer by directly targeting LIN28B. Specially, we found that the LIN28B protein levels were dramatically increased in lung cancer tissues, but its mRNA levels did not differ significantly, suggesting that a post-transcriptional mechanism is involved in LIN28B regulation. Interestingly, miR-203 overexpression was accompanied by massive upregulation of a group of miRNAs, especially let-7, and the let-7 expression level was concordant with the miR-203 expression in lung cancer tissues, implying its biological relevance. Furthermore, we showed that miR-203 played a critical role in inhibiting the proliferation and promoting the apoptosis of lung cancer cells by suppressing LIN28B and enhancing let-7 biogenesis. In summary, our results establish a novel mechanism by which miR-203, LIN28B and let-7 are tightly linked to form a regulatory network in lung cancer cells. The findings shed light on the role of a specific miRNA as a modulator of miRNA biogenesis and provide basis for developing new strategies for lung cancer therapy.