Macromolecular Nano-Assemblies for Enhancing the Effect of Oxygen-Dependent Photodynamic Therapy Against Hypoxic Tumors.

In oxygen (O2)-dependent photodynamic therapy (PDT), photosensitizers absorb light energy, which is then transferred to ambient O2, and subsequently cytotoxic singlet oxygen (1O2) is generated. Therefore, the availability of O2 and the utilization efficiency of generated 1O2 are two significant factors that influence the effectiveness of PDT. However, tumor microenvironments (TMEs) characterized by hypoxia and limited utilization efficiency of 1O2 resulting from its short half-life and short diffusion distance significantly restrict the applicability of PDT for hypoxic tumors. To address these challenges, numerous macromolecular nano-assemblies (MNAs) have been designed to relieve hypoxia, utilize hypoxia or enhance the utilization efficiency of 1O2. Herein, we provide a comprehensive review on recent advancements achieved with MNAs in enhancing the effectiveness of O2-dependent PDT against hypoxic tumors.

Curcuminoids Modulated the IL-6/JAK/STAT3 Signaling Pathway in LoVo and HT-29 Colorectal Cancer Cells.

BACKGROUND: Curcuminoids, including curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin, are natural polyphenolic compounds that exhibit various biological properties, such as antioxidant, anti-inflammatory, and anticancer activities. Dysregulation of the interleukin (IL)-6-mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway is closely associated with the development of colorectal cancer (CRC). METHODS: Here, we have evaluated the modulation of the IL-6/JAK/STAT3 pathway of curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin in LoVo and HT-29 colorectal cancer cells with a single molecular array (Simoa), western blot analysis, real-time polymerase chain reaction (PCR), and pathway analysis system. RESULTS: The study showed that curcuminoids suppressed the amount of IL-6 in LoVo and HT-29 colorectal cancer cells. Meanwhile, curcuminoids inhibited the expression of inflammation regulator-related microRNA (miRNA). We also found that the expression of total STAT3 was downregulated by curcuminoids. Moreover, the pathway analysis system showed that curcuminoids inactivated the JAK/STAT3 signaling pathway. Taken together, we demonstrated that the anti-cancer activities of curcuminoids against colorectal cancer are due to the modulation of the IL-6/JAK/STAT3 cascade. CONCLUSION: Curcuminoids could be a promising anti-cancer agent for the treatment of human colorectal cancer.

Roles of MT-ND1 in Cancer.

The energy shift toward glycolysis is one of the hallmarks of cancer. Complex I is a vital enzyme complex necessary for oxidative phosphorylation. The mitochondrially encoded NADH: ubiquinone oxidoreductase core subunit 1 (MT-ND1) is the largest subunit coded by mitochondria of complex I. The present study summarizes the structure and biological function of MT-ND1. From databases and literature, the expressions and mutations of MT-ND1 in a variety of cancers have been reviewed. MT-ND1 may be a biomarker for cancer diagnosis and prognosis. It is also a potential target for cancer therapy.

Molecular fingerprints of nuclear genome and mitochondrial genome for early diagnosis of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer with high morbidity and mortality rates. Due to the heterogeneity of LUAD, its characteristics remain poorly understood. Exploring the clinical and molecular characteristics of LUAD is challenging but vital for early diagnosis. METHODS: This observational and validation study enrolled 80 patients and 13 healthy controls. Nuclear and mtDNA-captured sequencings were performed. RESULTS: This study identified a spectrum of nuclear and mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with diagnosis. The correlation coefficient for somatic mutations in cfDNA and patient-matched tumor tissues was high in nuclear and mitochondrial genomes. The mutation number of highly mutated genes was evaluated, and the Least Absolute Shrinkage and Selection Operator (LASSO) established a diagnostic model. Receiver operating characteristic (ROC) curve analysis explored the diagnostic ability of the two panels. All models were verified in the testing cohort, and the mtDNA panel demonstrated excellent performance. This study identified somatic mutations in the nuclear and mitochondrial genomes, and detecting mutations in cfDNA displayed good diagnostic performance for early-stage LUAD. Moreover, detecting somatic mutations in the mitochondria may be a better tool for diagnosing early-stage LUAD. CONCLUSIONS: This study identified specific and sensitive diagnostic biomarkers for early-stage LUAD by focusing on nuclear and mitochondrial genome mutations. This also further developed an early-stage LUAD-specific mutation gene panel for clinical utility. This study established a foundation for further investigation of LUAD molecular pathogenesis.

Quantitative detection of circulating MT-ND1 as a potential biomarker for colorectal cancer.

Liquid biopsy represents a diagnostic and monitoring tool and the circulating cell-free mitochondrial DNA (mtDNA) plays a vital role in tumor diagnosis and dynamic assessment. Colorectal cancer (CRC) is one of the most common fatal cancers worldwide. Mitochondrially encoded NADH dehydrogenase subunit 1 (MT-ND1) encodes the biggest subunit of respiratory complex I of mtDNA, and mutations in the MT-ND1 are common in CRC. We sought to determine if mutations in circulating MT-ND1 could be a potential biomarker for colorectal cancer. In this study, twenty-two CRC patients at Zhujiang Hospital were included. We mainly used droplet digital PCR to determine the mutation status of MT-ND1, combined with clinical data. In the experiment in vivo, cell-free mtDNA generally presented high concordance with tumor tissues. By quantitative PCR, the MT-ND1 content of plasma in CRC patients was significantly higher than that in healthy individuals (58.01 vs. 0.64, p=0.027). The detection of circulating MT-ND1 content and variants (m.3606 A>G, m.3970 C>T, m.4071 C>T, m.4086 C>T) in cfDNA showed a good correlation with predicted tumor response and progression to chemotherapy. In conclusion, the content and variants of circulating MT-ND1 may become a versatile tool for the diagnosis and monitoring of colorectal cancer.

eRNAs and Superenhancer lncRNAs Are Functional in Human Prostate Cancer.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males worldwide. lncRNAs (long noncoding RNAs) play a significant role in the occurrence and development of PCa. eRNAs (enhancer RNAs) and SE-lncRNAs (superenhancer lncRNAs) are important elements of lncRNAs, but the role of eRNAs and SE-lncRNAs in PCa remains largely unclear. In this work, we identified 681 eRNAs and 292 SE-lncRNAs that were expressed differentially in PCa using a microarray. We also found that eRNAs transcribed from active open chromatin had significantly higher expression than those from active closed chromatin, and SE-lncRNAs had a little higher expression than eRNAs. Next, we constructed a transcriptional regulation network that eRNA-related enhancer and the target genes shared the same TF-binding motifs. Further, we investigated whether CTCF played a role in mediating the transcriptional regulation network. eRNAs, especially those that regulate androgen response genes, may be candidates for prognostic biomarkers and therapy targets. Our work provides a new perspective for developing medical treatments and therapies for prostate cancer.

A novel small peptide as a targeting ligand for receptor tyrosine kinase Tie2.

Tie2 is an endothelium-specific receptor tyrosine kinase known to play an important role in tumor angiogenesis. We sought to identify a small peptide ligand against Tie2 for developing a delivery targeting agent. We used hydrophobic analysis and comparative sequence/structure analysis to select a minimal peptide based on angiopoietin-2 amino acid sequence. The resulting peptide named GA3(WTIIQRREDGSVDFQRTWKEYK) was synthesized and labeled with iodine-125 at the C-terminal tyrosine residue to characterize its binding capability. In in vitro binding assays, GA3 can not only specifically bind to SMMC7721-Tie2 but also compete with angiopoietin-2 in binding. Via mouse tail vein injection, 125I-labeled GA3 was found to favorably accumulate in SPC-A1 xenograft tumor tissues which positively express Tie2. These results demonstrated that GA3 may be useful as a drug or gene delivery ligand for targeted chemotherapy, radiotherapy, and gene therapy.

Construction of an EGF receptor-mediated histone H1(0)-based gene delivery system.

PURPOSE: To construct an EGF receptor (EGF-R)-mediated histone H1(0)-based gene delivery system for gene therapy. METHODS: A recombinant DNA containing histone H1(0), EGF-R ligand, and endosomalytic domains was constructed in a prokaryotic vector and expressed in E. coli. Expression of the beta-galactosidase (beta-gal) gene in the tumor cells and tissues was observed after transduction of the beta-gal gene packaged by purified fusion proteins in vitro and in vivo. RESULTS: As an extension of the research on previously reported chemically synthetic composite polypeptide gene delivery systems, this genetically engineered polypeptide has proved to be capable of targeting the beta-galactosidase (beta-gal) gene into EGF-R-positive cancer cells both in vitro and in vivo. We also studied the time course of beta-gal gene expression in tumor tissues delivered in vivo by this polypeptide vector. At 24 h after administration, expression of the beta-galactosidase gene in tumor reached peak levels. The dosage optimization of administered polyplex was also investigated. The optimal dose of polyplex per mouse was 1 microg DNA packaged by 3 microg of composite polypeptide. CONCLUSIONS: The genetically engineered polypeptide based on histone H1(0) is a promising gene delivery system targeting EGF-R.

[In vitro experimental study of gene therapy for ovarian cancer with thymidine kinase gene of herpes simplex virus mediated by a non-viral GE7 delivery system].

OBJECTIVE: To investigate gene transfer efficiency of a novel target non-viral vector GE7 and effects of herpes simplex virus thymidine kinase (HSV(1)-tk)/ganciclovir (GCV) mediated by it in vitro. METHODS: The epidermal growth factor receptor (EGF-R) target gene delivery system GE7 was constructed. Human ovarian cancer cell line CAOV3 was transfected in vitro with beta-galactosidase (beta-gal) as reporter gene and HSV(1)-tk gene as therapeutic gene using this gene delivery system. By means of the assay of X-gal staining, Northern blotting, cell growth-inhibiting curve and so on, the transferring efficiency of exogenous genes and killing effects are observed. RESULTS: It showed that gene transfer efficiency is over 80%. When 10 mg/L GCV was put into ovarian cells transfected with HSV(1)-tk gene, 95% of cells were killed, and the apoptosis ratio reached up to 30. CONCLUSIONS: The GE7 gene delivery system is an effective and safe delivery system. GE7/HSV(1)-tk/GCV therapeutic gene system is appraising for ovarian cancer.