Simultaneous targeting and suppression of heat shock protein 60 to overcome heat resistance and induce mitochondrial death of tumor cells in photothermal immunotherapy.

As the most aggressive and metastatic subtype of breast cancer, clinical demands of triple negative breast cancer (TNBC) have far not been met. Heat shock protein 60 (HSP60) is over expressed in tumor cells and impair the efficacy of photothermal therapy. In this work, a conjugate composed of self-designed peptide targeting HSP60 and gold nanorods was constructed, referred to as AuNR-P17. Results showed that AuNR-P17 was able to simultaneously down regulate the level of HSP60 and locate in the mitochondria where HSP60 is enriched in the tumor cells of TNBC, which also impeded the interaction between HSP60 and integrin α3, thereby reducing the tumor cells' heat tolerance and metastatic capabilities. At the same time, AuNR-P17 induced remarkable mitochondrial apoptosis when exposed to the laser irradiation of 808 nm. The dual functions of AuNR-P17 led to the decrement of BCL-2 and the activation of p53 and cleaved caspase-3. The danger associated molecular patterns (DAMPs) generated from the mitochondrial apoptosis elicited strong and long-term specific immune responses against TNBC in vivo and ultimately inhibited the tumor metastasis and recurrence with significantly prolonged survival (>100 days) on TNBC mice. In conclusion, this study demonstrated HSP60 a promising potential therapeutic target for triple negative breast cancer and exhibited powerful capacity of AuNR-P17 in photothermal immune therapy.

ISG15 Promotes Progression and Gemcitabine Resistance of Pancreatic Cancer Cells Through ATG7.

Chemoresistance is an obstacle of improving pancreatic cancer (PC) prognosis. However, the biological function of ISG15 in PC and whether it correlates with the resistance to chemotherapy are still unknown. Here, we aimed to reveal the clinical significance of ISG15 in PC and its regulatory mechanism in cancer progression and resistance to therapy. The level of ISG15, a protein involved in post-translational modifications, is elevated in PC tissues. Clinically, higher ISG15 expression correlates with higher PC grades, stronger resistance to treatment and poorer prognosis. Moreover, ISG15 promotes the proliferation, migration, invasion, colony formation of PC cells and resistance to Gemcitabine, a classic chemotherapeutics for PC, both in vitro and in vivo. ISG15 promotes progression and resistance to therapy in PC cells by binding to ATG7, reducing its degradation, and thereby leading to enhanced autophagy in PC cells. ISG15 may be used as both a potential diagnosis marker and sensitizer for chemotherapeutics such as Gemcitabine during PC intervention.

Comparative Proteomic Analysis of Irradiation-Induced Radioresistant Breast Cancer Cells Using Label-Free Quantitation.

BACKGROUND: Breast cancer poses severe threats to human health as radioresistance becomes increasingly prevalent. The mechanisms of radioresistance are hard to expound completely. This study aims to explore proteomic changes of radioresistance, which will help elucidate the potential mechanisms responsible for breast cancer radioresistance and explore potential therapeutic targets. METHODS: A radioresistant breast cancer cell line was established by repeated irradiation. Liquid Chromatograph Mass Spectrometer (LC-MS) was used to quantify protein expression. Proteomic changes associated with radioresistance were evaluated by proteomic analysis. Further, cell radioresistance and several identified proteins were verified in in vitro experiments. RESULTS: In the study, more than 3000 proteins were detected, 243 of which were identified as up-regulated proteins and another 633 as down-regulated proteins. Gene Ontology (GO) enrichment analysis indicated that these proteins were mainly expressed in the lysosome and ribosome, associated with coenzyme binding and the structural constituent of the ribosome, involved in mitotic cytokinesis and ribonucleoprotein complex biogenesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many biological processes were extensively altered, particularly spliceosome and thermogenesis. It is worth noting that the functions and pathways related to ribosomes were significantly enriched, therefore ribosomal proteins (RPL6 and RPS13) were identified through western blot and highly expressed in relatively radiosensitive cells. Additionally, several identified proteins, including S100A4, RanBP9, and ISG15, were also verified to be differentially expressed in different radiosensitive cells. CONCLUSIONS: Our results provide a framework for further studies into the mechanisms of radioresistance and serve as a basis to construct a predictive model of radioresistance in breast cancer. Ribosome may participate in the radioresistance of breast cancer, which provides new insights into the proteomic characteristics of the mechanisms of radioresistance.

Near-Infrared Light-Controlled MicroRNA-21-Loaded Upconversion Nanoparticles to Promote Bone Formation in the Midpalatal Suture.

Rapid maxillary expansion (RME) is a common therapy for maxillary transverse deficiency. However, relapses after RME usually occur because of insufficient bone formation. MicroRNA-21 (miR-21) was reported as an important post-transcriptional modulator for osteogenesis. Herein, a photocontrolled miR-21 (PC-miR-21)-loaded nanosystem using upconversion nanoparticles (UCNPs) modified with poly(ether imide) (PEI), i.e., UCNPs@PEI@PC-miR-21, was constructed to promote bone formation in the midpalatal suture. UCNPs@PEI was constructed as the light transducer and delivery carrier. The UCNPs@PEI@PC-miR-21 nanocomplexes have good aqueous dispersibility and biocompatibility. The in vitro cell experiment suggested that UCNPs@PEI could protect PC-miR-21 from biodegradation and release PC-miR-21 into the cytoplasm under near-infrared light (NIR) irradiation. Furthermore, UCNPs@PEI@PC-miR-21 upregulated the expression of the osteogenic key markers, ALP, RUNX2, and COL1A1, at the levels of both genes and proteins. Besides, the results of the in vivo RME mice models further corroborated that photocontrollable UCNPs@PEI@PC-miR-21 accelerated bone formation with upregulating osteogenic markers of ALP, RUNX2, and osteoprotegerin and inducing fewer osteoclasts formation. In conclusion, UCNPs@PEI@PC-miR-21 nanoparticles with a NIR light could facilitate the remote and precise delivery of exogenous miR-21 to the midpalatal suture to promote bone formation during RME. This work represents a cutting-edge approach of gene therapy to promote osteogenesis in the midpalatal suture during RME and provides a frontier scientific basis for later clinical treatment.

The prognostic value and biological functions of HFM1 in breast cancer.

Aim: HFM1 has been reported to be associated with meiosis and ovarian insufficiency, but its role in tumors remains unknown. This study aims to explore the functions and potential mechanism of HFM1 in breast cancer. Methods: Several databases, protein-protein interactions, gene ontology and the Kyoto Encyclopedia of Genes and Genomes were used for bioinformatic analysis. Tissue microarrays and cell viability assays were used to detect the expression of HFM1 and tamoxifen resistance, respectively. Results: HFM1 was downregulated in breast cancer with poor prognosis and may modulate DNA damage repair pathways and immune infiltration. Moreover, HFM1 may mediate ovarian steroidogenesis and participate in tamoxifen resistance of estrogen receptor-positive breast cancer cells. Conclusion: We presented a first study on biological functions and potential mechanisms of HFM1 in cancers.

The role and function of the protein HFM1 in tumors remains unknown. We explored the functions and potential mechanism of HFM1 in breast cancer through several known databases, clinical samples and cell experiments. We found that HFM1 was downregulated in breast cancer with a poor prognosis. HFM1 may mediate ovarian steroidogenesis and participate in tamoxifen resistance of estrogen receptor-positive breast cancer cells. Here we first put forward the relationship between HFM1 and the prognosis of breast cancer, and provided relevant clues for mechanism exploration.

CXC Chemokine Receptor Type 4 Antagonistic Gold Nanorods Induce Specific Immune Responses and Long-Term Immune Memory to Combat Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly challenging in its treatment because of the lack of the targeted markers. TNBC patients are not able to acquire benefits from endocrine therapy and targeted therapy except for chemotherapy. CXCR4 is highly expressed on TNBC cells that mediated the tumor cell metastasis as well as proliferation by the response of its ligand CXCL12, therefore holding promising potential of a candidate target for the treatment. In this work, a novel conjugate of CXCR4 antagonist peptide E5 and gold nanorods was fabricated (AuNRs-E5), which was applied to murine breast cancer tumor cells and an animal model, aiming to induce endoplasmic reticulum stress by endoplasmic reticulum-targeted photothermal immunological effects. Results showed that AuNRs-E5 could induce much more generation of damage-related molecular patterns in 4T1 cells under laser irradiation than AuNRs, which significantly promoted the maturation of dendritic cells and stimulated systematic anti-tumor immune responses by enhancing the infiltration of CD8+T cells into the tumor and tumor-draining lymph node, downregulating the regulatory T lymphocytes, and upregulating M1 macrophages in tumors, reversing the microenvironment from "cold" tumors to "hot" tumors. The administration of AuNRs-E5 with laser irradiation not only inhibited the tumor growth significantly but also exerted specific long immune responses to the triple-negative breast cancer tumor cells, which led to the prolonged survival of the mice and the specific immunological memory.

Comprehensive Evaluation of Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 and Their Combined Immunotherapy in Clinical Trials: A Systematic Review and Meta-analysis.

Immunotherapy with immune checkpoint inhibitor (ICI) drugs is gradually becoming a hot topic in cancer treatment. To comprehensively evaluate the safety and efficacy of ICI drugs, we employed the Bayesian model and conducted a network meta-analysis in terms of progression-free survival (PFS), overall survival (OS) and severe adverse events (AEs). Our study found that treatment with ipilimumab was significantly worse than standard therapies in terms of PFS, whereas treatment with cemiplimab significantly improved PFS. The results also indicated that cemiplimab was the best choice for PFS. Treatment with nivolumab, pembrolizumab and nivolumab plus ipilimumab significantly improved OS compared to standard therapies. In terms of OS, cemiplimab was found to be the best choice, whereas avelumab was the worst. In terms of severe AEs, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab all significantly reduced the risk of grade 3 or higher AEs compared to standard therapy. The least likely to be associated with severe AEs were as follows: cemiplimab, avelumab, nivolumab, atezolizumab, and camrelizumab, with nivolumab plus ipilimumab to be the worst. Therefore, different ICI drug therapies may pose different risks in terms of PFS, OS and severe AEs. Our study may provide new insights and strategies for the clinical practice of ICI drugs.

A comprehensive bioinformatic analysis of RanBP9 expression and its relation to prognosis in human breast cancer.

Aim: To explore the role of RanBP9 in breast cancer. Materials & methods: Oncomine, TIMER, GEPIA, UALCAN, c-BioPortal databases and tissue microarray analysis were used in this study. Results: The expression level of RanBP9 is elevated in breast cancer tissues, which is associated with poor prognosis in breast cancer patients. RanBP9 exhibits genetic alterations and a decreased methylation level in cancer tissues. RanBP9 may also regulate cell cycle progression and is linked to tumor purity and the infiltrating levels of immune cells. Conclusions:RanBP9 may correlate with prognosis and immune infiltration in breast cancer, laying the foundation for future studies on the potential role of RanBP9 in breast cancer.

Lay abstract RanBP9 has diverse function in various tumor types. However, the role of RanBP9 in breast cancer remains to be explored. In this study, we investigated the gene expression of RanBP9 using databases and clinical samples. We found the expression level of RanBP9 is raised in breast cancer tissues and is associated with poor prognosis for breast cancer patients. RanBP9 may be involved in the regulation of the cell cycle and related to tumor immunity. Overall, we found that RanBP9 may correlate with prognosis and immune infiltration of breast cancer, laying the foundation for future studies on the potential role of RanBP9 in breast cancer.

Plasma Exosome-Derived SENP1 May Be a Potential Prognostic Predictor for Melanoma.

OBJECTIVE: To evaluate plasma exosome-derived SUMO-specific protease (SENP)1 levels and assess their prognostic value in melanoma. PATIENTS AND METHODS: We extracted exosomes from the plasma of 126 melanoma patients, and identified them with transmission electron microscopy, nanoparticle tracking analysis and western blotting. The plasma exosome-derived SENP1 levels of melanoma patients and healthy controls were detected with ELISA. RESULTS: Plasma exosome-derived SENP1 levels in melanoma patients were significantly upregulated than in healthy controls (P < 0.001). Plasma exosome-derived SENP1 levels in melanoma patients with tumor size >10 cm, located in the mucosa or viscera, with Clark level IV/V, with lymph node metastasis, and TNM stages IIb-IV were significantly higher than in patients in with tumor size <10 cm, located in the skin, with Clark level I-III, without lymph node metastasis, and TNM stages IIb-IV (all P < 0.05). Disease-free survival (DFS) and overall survival (OS) were worse in melanoma patients who had higher plasma exosome-derived SENP1 levels than lower plasma exosome-derived SENP1 levels (both P < 0.001). Area under the receiver operating characteristic curve (AUROC) of plasma exosome-derived SENP1 for predicting 3-year DFS of melanoma patients was 0.82 [95% confidence interval (CI): 0.74-0.88], with a sensitivity of 81.2% (95% CI: 69.9-89.6%) and specificity of 75.4% (95% CI: 62.2-85.9%). The AUROC of plasma exosome-derived SENP1 for predicting 3-year OS of melanoma patients was 0.76 (95% CI: 0.67-0.83), with a sensitivity of 95.7% (95% CI: 85.5-99.5%) and specificity of 62.0% (95% CI: 50.4-72.7%). CONCLUSIONS: Melanoma patients with higher plasma exosome-derived SENP1 levels had worse DFS and OS. The plasma exosome-derived SENP1 levels may be a potential prognostic predictor for 3-year DFS and 3-year OS of melanoma.

Liquid biopsy and their application progress in head and neck cancer: focus on biomarkers CTCs, cfDNA, ctDNA and EVs.

Head and neck cancer (HNC) is the sixth leading cause of cancer death worldwide. Due to the low early diagnosis rate of HNC, local recurrence and high distant metastasis rate are the main reasons for treatment failure. Therefore, it is important to establish a method of diagnosis and monitoring, which is convenient, safe, reproducible, sensitive and specific. Compared with tissue biopsy, liquid biopsy is an emerging biopsy technique, which has the advantages of re-sampling, noninvasive and cost-effectiveness, and has shown good diagnostic and prognostic value in studies for various types of malignant solid tumors. This review introduces liquid biopsy, its research progress and prospects in HNC including early diagnosis, staging, grading, prognosis assessment and disease surveillance.

ATM Expression Is Elevated in Established Radiation-Resistant Breast Cancer Cells and Improves DNA Repair Efficiency.

Repair of damaged DNA induced by radiation plays an important role in the development of radioresistance, which greatly restricts patients' benefit from radiotherapy. However, the relation between radioresistance development and DNA double-strand break repair pathways (mainly non-homologous end joining and homologous recombination) and how these pathways contribute to radioresistance are unclear. Here, we established a radioresistant breast cancer cell line by repeated ionizing radiation and studied the alteration in DNA repair capacity. Compared with parental sham-treated cells, radioresistant breast cancer cells present elevated radioresistance, enhanced malignancy, increased expression of Ataxia-telangiectasia mutated (ATM), and increased DNA damage repair efficiency, as reflected by accelerated γ-H2AX kinetic. These defects can be reversed by ATM inhibition or ATM knockdown, indicating a potential link between ATM, DNA repair pathway and radiosensitivity. We propose that cancer cells develop elevated radioresistance through enhanced DNA damage repair efficiency mediated by increased ATM expression. Our work might provide a new evidence supporting the potential of ATM as a potential target of cancer therapy.

MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment.

Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.