Human Cancer Research Articles

PGRN mediates the crosstalk between ovarian cancer cells and CAFs and reshapes tumor immune microenvironment.

Melanoma is one of the most lethal forms of skin cancer, driving continuous research efforts to discover effective therapeutic strategies. Phytochemicals are promising for antimelanoma drug development because of their multitarget bioactivities. 9-Methoxycamptothecin (MCPT), a plant-origin compound, has demonstrated potent anticancer activity against various human cancers; however, its inhibitory effects on melanoma and the underlying molecular mechanisms remain incompletely understood. In this research, human melanoma cell lines (A375, SKMEL28) were treated with MCPT. Cell proliferation was evaluated using MTT and clonogenic assays. Cell cycle and apoptosis were assessed by flow cytometry. The MCPT-induced DNA damage in melanoma cells was observed via immunofluorescence staining of γ-H2AX. Protein expression was analyzed by western blotting. Proliferating cell nuclear antigen associated factor 15 (PAF15) was overexpressed via lentiviral transduction to evaluate its functional role in MCPT response. The antimelanoma effect of MCPT in vitro was studied in BALB/c nude mice bearing subcutaneous tumors from A375 cells. The results showed that MCPT suppressed melanoma cell proliferation via inducing the G2/M phase cell cycle arrest. Meanwhile, MCPT induces caspase-dependent apoptosis and DNA damage in melanoma cells. In vivo, MCPT effectively inhibited the growth of melanoma xenografts. Crucially, these MCPT-mediated effects were partly rescued by exogenous PAF15 overexpression. In conclusion, MCPT exerts antimelanoma effects by inhibiting proliferation, inducing cell cycle arrest, DNA damage, and apoptosis. Importantly, these effects are critically mediated through the downregulation of PAF15.

Co-targeting CDK4/6 enhances anti-cancer activity and alleviates immune-related adverse events of anti-PD-1 antibody for breast cancer.

The antiproliferative effect of [AuCl(tmp-terpy)](PF6)2 (1), [PtCl(tmp-terpy)](CF3SO3) (2), [MnCl2(tmp-terpy)] (3), and 4'-(3,4,5-trimethoxy-phenyl)-2,2':6',2″-terpyridine (tmp-terpy) was analyzed in sensitive and doxorubicin-resistant (DoxR) colorectal cancer (CRC) cell lines and in normal primary human fibroblasts. Comprehensive studies were performed for 1 and tmp-terpy, showing the strongest cytotoxicity in HCT116DoxR 2D cells and having the capability to induce the loss of cell viability in 3D HCT116DoxR spheroids. Complex 1 internalizes CRC-resistant cancer cells and increases the number of reactive oxygen species (ROS), triggering cell death by apoptosis and autophagy. Changes in protein expression levels of HCT116DoxR cells exposed to 1 and tmp-terpy primarily affect protein folding, apoptosis, and stress response, consistent with the observed induction of programmed cell death and ROS. The combination of 1 or tmp-terpy with oxaliplatin (OX) and cisplatin (Cis) shows cytotoxic effects in 3D CRC-resistant spheroids. No in vivo toxicity in a chicken embryo is observed, even when 1 is combined with an OX and Cis.

Structural Variants (SVs) are defined as genomic variants affecting more than 500 base pairs. They include deletions, insertions, inversions, translocations, tandem repeats, and copy number variations (CNVs). These SVs contribute significantly to genetic complexity and are involved in human evolution, genetic disorders, and cancer. Over 50% of the SVs cannot be detected due to limitations in methods and technologies. The short-read sequencing technologies are limited in detecting single-nucleotide variants and fail to resolve complex, repetitive and intronic regions. The advent of long-read sequencing (LRS) technologies, such as Oxford Nanopore and PacBio platforms, has revolutionised SV detection. These platforms allow accurate characterisation of diverse variant types, from simple deletions to complex chromothripsis events, and support de novo assembly, haplotype phasing, and resolution of repetitive or structurally complex genomic regions. One major outcome is the completion of the telomere-to-telomere (T2T) human reference genome. This review summarises recent advances in LRS for SV detection, including sequencing platforms, bioinformatic tools, analysis, and validation strategies. The clinical applications, especially in rare disease diagnostics, are illustrated with two novel cases which were successfully resolved using both LRS approaches. Long-read sequencing can solve the limitations of short-read sequencing in SV detection, providing better insights into genome disorders. It enables the detection of repeat and difficult-to-resolve regions of the genome and facilitates clinical diagnoses to base-level breakpoint detection. Despite challenges such as high cost, data interpretation, and clinical linking, continued advancements are elevating LRS as an invaluable tool in precision genomic medicine.

ObjectiveTo explore the difference of metabolites between human papillomavirus (HPV) infection and the occurrence and development of cervical cancer based on non-targeted metabolomics.MethodsBetween August 2022 and August 2023, 20 women of childbearing age at the Third Affiliated Hospital of Kunming Medical University, including the HPV-negative control, LSIL (HPV infection), HSIL (cervical intraepithelial neoplasia [CIN2-3]), and cervical cancer groups, were selected as research participants. Ultra-high-performance liquid chromatography and SCIEX mass spectrometry (TripleTOF 6600+, USA) were used to separate and detect the metabolites.ResultsAccording to the results of the differential metabolite analysis, the KEGG pathway was enriched. The most obvious enrichment pathway in the CIN2-3 group compared with the HPV-negative and HPV-positive groups was the steroid hormone pathway; the most obvious enrichment pathway in the cervical cancer group compared with the HPV-negative group was the steroid hormone pathway. Compared with HPV-negative group, the most obvious enrichment pathway in the CIN2-3 group was the glycerophosphate metabolism pathway. Compared with CIN2-3 and HPV-positive group, the most obvious enrichment pathway in the cervical cancer group was the sphingolipid metabolism pathway, followed by the steroid biosynthesis and amino sugar and nucleotide metabolism pathways. Compared with the HPV-negative group, the most obvious enrichment pathway in the cervical cancer group was the steroid biosynthesis pathway, followed by the sphingolipid metabolism pathway. 19-Hydroxytestosterone is involved in the synthesis of steroid hormones. Cerebroside B is involved in sphingolipid metabolism. Potassium acetate is involved in protein digestion and absorption. Methylarsonate is involved in chemical carcinogenesis - reactive oxygen species.ConclusionThe expression levels of 19-Hydroxytestosterone, cerebroside B, potassium acetate and methylarsonate are downregulated with the aggravation of cervical lesions and can be used as potential tumor markers for cervical cancer.

miRNA-21-5p and miRNA-155-5p have emerged as two promising biomarkers in body fluids during the early stages of lung cancer. This study focused on designing a dual-target optical biosensor for the simultaneous detection of miRNA-21 and miRNA-155. DNA hairpin probes and metal nanoclusters are the materials used in this design. Light-emitting gold nanoclusters (AuNCs) and copper-silver nanoclusters (Cu/AgNCs) were located on hairpin probes to achieve fluorescence-based detection. The biosensor leverages the distinct fluorescence properties of these nanoclusters to detect target miRNAs (miRNA-21 enhances the emission of Cu/AgNCs, while miRNA-155 quenches the emission of AuNCs). The biosensor demonstrated remarkable sensitivity toward miRNA-21 and miRNA-155. Detection limits were 1pM and 5pM, and linear response ranges were 15-140pM and 15-125pM for miRNA-21 and miRNA-155, respectively. The response of the nanobiosensor was validated by RT-qPCR as the gold standard method in analyses of miRNAs in human serum samples and lung cancer cells. The obtained results confirmed the accuracy and reliability of the biosensor. Compared to existing biosensors, the proposed design avoids complex surface modifications and enzyme usage, ensuring cost-effectiveness and operational simplicity.

Systematic review and meta-analysis corrected for history of smoking tobacco identifies type 1 diabetes as a possible risk factor for bladder cancer.

ABSTRACT We report the design and synthesis of a new pyrimidine‐based organoplatinum (II) complex ( 3 ), constructed over three consecutive steps starting from 4,6‐dichloropyrimidine. This flexible precursor acted as a key acceptor tecton to compose the self‐assembly of three distinct ionic [2 + 2] macrocycles ( M 1 – M 3 ) in high yields through coordination with neutral N‐donor ligands. Comprehensive spectroscopic and analytical techniques such as FT‐IR, NMR, and HRMS were employed to validate the purity, symmetry, and structural integrity of the macrocycles. Notably, the appearance of sharp singlets in 31 P NMR spectra and the presence of a single diffusion trace in 1 H‐DOSY NMR unequivocally confirmed the formation of discrete, well‐defined assemblies. High‐resolution mass spectra further supported this, revealing the signature [M‐3NO 3 ] 3+ peaks for all macrocycles. MTT assay was performed to evaluate the cytotoxic potential of these compounds against human breast cancer cell line MCF‐7 and human normal breast epithelial cell line MCF‐10A. The findings revealed that the macrocycles exhibited greater cytotoxicity than the precursor molecule and cisplatin in MCF‐7 cells. Furthermore, all the compounds showed much lesser cytotoxicity toward normal MCF‐10A cells. These results indicate that self‐assembled, charged organoplatinum macrocycles manifest enhanced anticancer potential and may serve as promising scaffolds for the development of next‐generation chemotherapeutic agents.

The aim of this study was to investigate the effect of Chamaejasmenin B (CHB), a phytochemical, on human pancreatic cancer cell line (MIA PaCa-2). CCK-8 test was performed to evaluate the cytotoxic effect of CHB. To elucidate the molecular mechanism of CHB, expression levels of important genes in the cell cycle and apoptosis pathways were evaluated by qPCR and Western blot analysis. In addition, the effects of CHB on the colony formation capacity of cells, total oxidant and total antioxidant levels were also evaluated. The IC50 dose of CHB on MIA PaCa-2 cells was found as 647 µM at 48h. After CHB treatment in MIA PaCa-2 cells, expressions of BAX, CASP3, CASP7, CYCS, FADD, FAS, CCND2 and P53 genes were significantly increased. However, a decrease in the expressions of CDK4, CDK6, CCND1 and CCND3 genes was observed. In addition, an elevation in CASP3 and P53 protein levels and a decrease in the level of CCND1 protein were determined. CHB treatment significantly suppressed the colony formation capacity in MIA PaCa-2 cells. In addition to these, an increase in total antioxidant levels was observed. These findings suggest that CHB seems to be a promising anticancer therapeutic agent in the treatment of pancreatic cancer.

Abstract In the modern era, pollutants like NO 2 , SO 2 , O 3 , and particulate matter threaten skin health by generating ROS and causing DNA damage, raising cancer risk. Due to the toxicity of conventional chemotherapy, plant‐based nanotherapeutics offer a safer, eco‐friendly, and more targeted treatment alternative.The present work deals with synthesize of palmitic acid coated titatinum dioxide nanoparticles (PA‐TiO 2 NPs) using the aqueous extract of Ceratopteris thalictroides (L.) Brongn, with the aim of evaluating their anticancer activity against human epidermoid carcinoma (A431) cell line. X‐ray diffraction (XRD) confirmed the anatase crystalline phase with a crystallite size of 6.23 nm. The Raman spectra revealed the presence of four active Raman modes, with peaks at 144, 399, 519, and 639 cm −1 confirming the anatase phase of PA‐TiO 2 NPs. Brunauer–Emmett–Teller (BET) analysis of PA‐TiO 2 suggests a surface area of 28.850 m 2 /g. XPS analysis showed Ti 3 ⁺/Ti⁴⁺ states and oxygen vacancies. Cytotoxicity assays confirmed a dose‐dependent inhibition of A431 cells, with an IC 50 value of 45.0 µg/mL. Flow cytometry revealed that PA‐TiO 2 nanoparticles induced cell cycle arrest at the S and G 2 /M phases and increased apoptotic cell populations in A431 cells. These findings highlight PA‐TiO 2 NPs as promising nanotherapeutic candidates for skin cancer treatment.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood, and effective treatments remain to be discovered. Here, we report that loss of the nuclear receptor ERRγ promotes neuroendocrine differentiation in a Pten-deficient mouse model of prostate adenocarcinoma. These findings were recapitulated in advanced cellular and xenograft models of human prostate cancer. Critically, we show that ERRγ gain of function can reverse instilled NEPC features accompanied by suppression of growth and oncogenic metabolic reprogramming. Activation of a neuroendocrine transcriptional program enabled by ERRγ deficiency unveiled a targetable vulnerability exploited by the combined pharmacological inhibition of EZH2 and RET kinase that effectively inhibited the growth of ERRγ-deficient tumor organoids and cells. Collectively, our findings demonstrate that ERRγ downregulation facilitates prostate cancer adeno-to-neuroendocrine transformation and offer potential therapeutic strategies to prevent/treat the development of poor outcome NEPC.

Despite shared genetic driver alterations and histology, the genomic fidelity of most mouse tumor models, including those genetically engineered (GEMM), to their human counterparts is unknown. In this study, we developed MiMouse, a mouse comprehensive genomic profiling panel for high-throughput credentialing applicable to routine formalin-fixed, paraffin-embedded tumors. Through simulation/validation, we focused on considerations for cross-species mutation prioritization, strain determination, and aneuploidy detection. Using MiMouse, we profiled >250 tumors from high-grade serous carcinoma GEMMs based on conditional inactivation of Brca1 (B), Trp53 (P), Pten (Pt), Rb1 (R), and/or Nf1 (N) and a colorectal carcinoma GEMM based on conditional inactivation of Apc, Kras, and/or P. We confirmed increased genomic instability in high-grade serous carcinoma tumors, with BPPt cancers having both the shortest latency and the least genomic instability. In colorectal cancer, focusing on fidelity to human colorectal cancer aneuploidy events, our results highlighted the critical importance of synteny in transgenic studies, as not only was loss of mouse chromosome 18 (containing the tumor suppressor gene Smad4) a significant aneuploidy event (18%), additional tumors harbored focal Smad4 copy loss, potentially due to the mouse-specific proximity of Apc (mouse and human chromosomes 18 and 5, respectively). Likewise, mouse chromosome 5, the only significantly gained (46%) chromosome in our colorectal cancer models, has syntenic blocks from human chromosomes 7p, 7q, and 13q, including Cdx2, which is both a lineage-specific colorectal cancer oncogene and the colorectal cancer GEMM promoter source. Given the importance of mice to translational cancer research, this study highlights the considerations and utility of approaches for comprehensive genomic credentialing.Significance:The genomic fidelity of most mouse tumor models is unknown. Considering cross-species issues, we develop MiMouse for high-throughput genomic credentialing and profile >250 tumors from fallopian tube and colorectal tumor models.

[This retracts the article DOI: 10.2147/CMAR.S185789.].

Antibodies against αGal are among the most abundant natural antibodies in humans and have been exploited in cancer immunotherapy, with their efficacy partly attributed to complement activation. We aim to enhance this response by employing Properdin (FP), the only known positive complement regulator. We expressed a membrane-anchored properdin (mFP) on mouse and human pancreatic cancer cells and assessed its ability to enhance αGal-mediated complement activation. We showed here that ectopic expression of mFP on Panc02 cells increased the deposition level of C3 in vitro and induced more potent complement-dependent cytotoxicity in the presence of human complement source. In an immunized Ggta1 knockout mouse model, which has circulating anti-αGal antibodies as a mimicry of the human system, mFP expression conferred significantly delayed tumor growth and was associated with marked remodeling of the immune landscape in the tumor microenvironment (TME). Specifically, we observed a marked increase in conventional type 1 dendritic cells, a reduction in tumor-associated monocytes/macrophages with a shift toward a pro-inflammatory phenotype, and a transition of CD8+ T cells toward a progenitor-exhausted state. Reconfiguring the structure of mFP to create an artificial C3 convertase binding site and incorporating an intracellular oligomerization domain improved target cell killing and phagocytosis by monocytes in a human whole blood loop model. These findings suggest that amplifying complement activation can delay tumor growth and alter the TME in the context of a murine pancreatic cancer model. Furthermore, we have developed a novel membrane-bound oligomerized FP functional unit, which effectively elicits robust complement activation.

The efficiency of electrochemiluminescence (ECL) emission relies heavily on the spatial proximity between luminophores and coreactant promoters. In conventional ternary systems, the diffusion-driven separation of components in solution often leads to energy loss and lower ECL efficiency. In this work, a self-enhanced lanthanide metal-organic framework (Ln-MOF) emitter, CuTb-BTC@AgNPs (CTBA), was constructed using Tb3+ as the luminophore, Cu2+ as the coreactant promoter, and Ag nanoparticles (AgNPs) as the electrical conductivity enhancer. An appropriate colocalization of these components significantly shortened the electron transfer distance between the luminescent group and the coreactant promoter, thereby enhancing the ECL efficiency. To modulate the signal, a Pd@Cu2O quencher, which has a broad UV-Vis absorption range, was introduced for resonance energy transfer (RET)-based suppression. A dual-output toehold-mediated strand displacement (TMSD) strategy was employed to enable target recycling and "on-off" signal control. Using microRNA-155 (miR-155), a biomarker implicated in multiple cancers, as a model target, the biosensor exhibited a wide linear detection range from 10 aM to 1 nM and an ultralow detection limit of 4.7 aM. It also had excellent specificity and achieved high recovery rates when applied to detect human serum and cancer cell samples. Overall, this work describes a robust strategy for integrating Ln-MOF emission platforms with nucleic acid amplification, presenting a powerful tool for the ultrasensitive detection of clinically relevant miRNA.

Background/AimThe adverse side effects associated with chemotherapeutic agents have prompted the exploration of natural compounds as adjuvants to chemotherapy, offering more effective therapeutic alternatives. Licoricidin, a bioactive constituent of licorice, possesses diverse pharmacological properties. However, the antitumor mechanisms underlying the therapeutic effects of Licoricidin combined with paclitaxel in cervical cancer remain unclear and further investigations are warranted.Materials and MethodsCell growth and apoptosis were assessed using the MTT assay and Annexin V/PI staining. Endoplasmic reticulum (ER) stress was evaluated using the ER-ID assay. The expression of apoptosis- and ER stress-related proteins in response to the combined treatment was analyzed using western blotting.ResultsCombined treatment with licoricidin and paclitaxel effectively inhibited cell growth and induced apoptosis in human HeLa and C-33A cells. We further revealed that this combined treatment increased the expression of apoptotic proteins (c-PARP, Bax, and DR5) while decreasing the expression of pro-caspase proteins (pro-caspase-3 and pro-caspase-9) in HeLa cells. In addition, the combined treatment induced ER stress, as evidenced by decreased expression levels of ERp44, ERp57, and ERp72, whereas the expression of GRP78 was increased in HeLa cells.ConclusionThe combination of licoricidin and paclitaxel induced ER stress-mediated apoptosis and may serve as a potential antitumor therapeutic strategy against human cervical cancer cells.

Colorectal cancer treatment primarily relies on chemotherapy, which often causes significant side effects. Sacha inchi, a plant known in traditional medicine, has shown promise in various therapeutic applications. However, despite its potential, the specific mechanisms remain poorly understood, particularly regarding its husk components. This study investigates sacha inchi husk extract’s chemical properties and its effects on human colorectal cancer cells. GC/MS and LC/MS analyses revealed a rich profile of phenolic and flavonoid compounds, with naringenin and lidocaine as predominant components. The extract demonstrated significant dose-dependent inhibition of colorectal cell migration, invasion, and colony formation while exhibiting no cytotoxicity toward normal colon epithelial cells. Transcriptomic and proteomic analyses showed downregulation of migration- and invasion-related genes in cancer cells, and Western blot analysis confirmed reduced expression of MMP2, MMP9, and N-cadherin. EGFR pathway analysis showed decreased expression of RAS (−0.2-fold), MAK (−0.26-fold), and ERK (−0.54-fold) genes, indicating suppression of epithelial–mesenchymal transition (EMT). These findings demonstrate that sacha inchi husk extract effectively inhibits metastasis in colorectal cancer cells through the upstream (EGFR) and downstream (EMT) pathways, suggesting its potential as a dietary supplement or therapeutic agent for colorectal cancer treatment. Our research provides evidence for the development of natural, less toxic alternatives.

Background/AimZinc finger CCCH-type containing 12A (ZC3H12A), also known as monocyte chemotactic protein-induced protein 1, has emerged as having a potential role in the landscape of some human cancer types, contributing to anti-tumorigenesis through signaling pathways of inflammation, apoptosis, autophagy and angiogenesis. However, its specific impact on the prognosis of oral squamous cell carcinoma (OSCC) remains to be investigated.Patients and MethodsWe conducted in-vitro cell models in a pilot study and performed a retrospective cohort study involving 242 patients with OSCC to unravel the association between ZC3H12A expression level and oral cancer prognosis during 3, 5, and 10-year follow-up.ResultsThe findings showed that endogenous ZC3H12A expression was decreased in both the malignant (BQO) and highly metastatic (HSC-3-M3) OSCC cell lines compared to dysplastic oral keratinocytes (DOK) and the parental cell line of HSC-3-M3 (HSC-3). The analysis of clinical cancerous tissue arrays from patients with OSCC showed a significant association between complete loss of ZC3H12A expression and heightened cancer mortality, particularly at 3 and 5 years. Moreover, the complete loss of ZC3H12A expression may be associated with increased risk of lymph node involvement in OSCC.ConclusionOur investigation suggests that the complete loss of ZC3H12A expression exacerbated the unfavorable prognosis of OSCC in this Taiwanese population, but further study on elucidating the gradual decline of ZC3H12A expression in OSCC is imperative.

Canine adenovirus type 2 (CAdV-2) infects the respiratory tissues of dogs and induces canine infectious laryngotracheitis. CAdV-2 has a high incidence of infection and is easily co-infected with other viruses. Moreover, CAdV-2 is a mammalian adenovirus with characteristics similar to those of Human Adenovirus Type 5 (HAdV-5), making it a promising candidate for recombinant vaccine development and gene therapy applications. In this study, we isolated and identified a CAdV-2 strain (CAV-HN45) and investigated its growth characteristics and viral tropism by evaluating its infection efficiency in various cell lines. Our findings demonstrate that CAV-HN45 can effectively infect cells of swine, canine, and human origin. In vitro , CAV-HN45 efficiently infected HeLa cells and showed selective infectivity toward human cervical cancer cells, although replication capacity declined after serial passages. This study provides a reference for the future studies on adenovirus vaccine vectors with high selective expression, potentially offering promising applications in the treatment of human cancers.