Lung cancer cell-intrinsic IL-15 promotes cell migration and sensitizes murine lung tumors to anti-PD-L1 therapy.

BACKGROUND: IL-15 plays a vital role in enhancing NK cell- and T-cell-mediated antitumor immune responses; however, the direct effect of IL-15 on tumor cells has not been fully elucidated. Herein, we investigated the effect of IL-15 on lung adenocarcinoma cells. METHODS: Silencing and overexpression techniques were used to modify endogenous IL-15 expression in tumor cells. Transwell assays were used to assess tumor cell migration and invasion; a live-cell analysis system was used to evaluate cell motility; cellular morphological changes were quantified by confocal fluorescence microscopy; the molecular mechanisms underlying the effect of IL-15 on tumor cells were analyzed by western blotting; and RhoA and Cdc42 activities were evaluated by a pulldown assay. NCG and C57BL/6 mouse models were used to evaluate the functions of IL-15 in vivo. RESULTS: Cancer cell-intrinsic IL-15 promoted cell motility and migration in vitro and metastasis in vivo via activation of the AKT-mTORC1 pathway; however, exogenous IL-15 inhibited cell motility and migration via suppression of the RhoA-MLC2 axis. Mechanistic analysis revealed that both the intracellular and extracellular IL-15-mediated effects required the expression of IL-15Rα by tumor cells. Detailed analyses revealed that the IL-2/IL-15Rß and IL-2Rγ chains were undetected in the complex formed by intracellular IL-15 and IL-15Rα. However, when exogenous IL-15 engaged tumor cells, a complex containing the IL-15Rα, IL-2/IL-15Rß, and IL-2Rγ chains was formed, indicating that the differential actions of intracellular and extracellular IL-15 on tumor cells might be caused by their distinctive modes of IL-15 receptor engagement. Using a Lewis lung carcinoma (LLC) metastasis model, we showed that although IL-15 overexpression facilitated the lung metastasis of LLC cells, IL-15-overexpressing LLC tumors were more sensitive to anti-PD-L1 therapy than were IL-15-wild-type LLC tumors via an enhanced antitumor immune response, as evidenced by their increased CD8+ T-cell infiltration compared to that of their counterparts. CONCLUSIONS: Cancer cell-intrinsic IL-15 and exogenous IL-15 differentially regulate cell motility and migration. Thus, cancer cell-intrinsic IL-15 acts as a double-edged sword in tumor progression. Additionally, high levels of IL-15 expressed by tumor cells might improve the responsiveness of tumors to immunotherapies.

Histological evaluation of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: Correlation with Drum Tower Severity Scoring.

BACKGROUND: Hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids (PA-HSOS) is a complication of drug-induced liver damage. Few studies have examined the relationship between pathological changes and clinical circumstances in PA-HSOS. The Drum Tower Severity Scoring System (DTSS) was developed using prognostic indicators from clinical treatment outcomes. We hypothesized that the severity of pathological damage is consistent with DTSS. AIMS: We aimed to improve our understanding and assessment of vascular liver injury disease histopathology by studying larger sample sizes of human histopathological samples. We also wanted to confirm the link between histopathological findings and DTSS. METHODS: The study included 62 patients with PA-HSOS who underwent transjugular liver biopsy. Their hepatic pathological tissues were evaluated. Analyses of linear regression and Spearman's correlation were employed to examine the relationship between DTSS and pathological characteristics. RESULTS: Clinical performance and the DTSS score were used to determine histopathological severity. The sinusoidal congestion area (SCA), central venous endothelial injury (CVEI), and fibrinoid exudation in congestion foci (FECF) were significant indicators. SCA was linearly related to the DTSS score. CONCLUSION: Our findings show that hepatic pathological characteristics correlate with DTSS scores in PA-HSOS. SCA, CVEI, and FECF may be helpful for determining PA-HSOS severity.

Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma.

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

TGFß Antagonizes IFNγ-Mediated Adaptive Immune Evasion via Activation of the AKT-Smad3-SHP1 Axis in Lung Adenocarcinoma.

IFNγ-mediated signaling in tumor cells can induce immunosuppressive responses and cause tumor resistance to immunotherapy. Blocking TGFß promotes T lymphocyte infiltration and turns immunologically cold tumors into hot tumors, thereby improving the efficacy of immunotherapy. Several studies have shown that TGFß inhibits IFNγ signaling in immune cells. We thus sought to determine whether TGFß affects IFNγ signaling in tumor cells and plays a role in the development of acquired resistance to immunotherapy. TGFß stimulation of tumor cells increased SHP1 phosphatase activity in an AKT-Smad3-dependent manner, decreased IFNγ-mediated tyrosine phosphorylation of JAK1/2 and STAT1, and suppressed the expression of STAT1-dependent immune evasion-related molecules, e.g., PD-L1, IDO1, herpes virus entry mediator (HVEM), and galectin-9 (Gal-9). In a lung cancer mouse model, dual blockade of TGFß and PD-L1 led to superior antitumor activity and prolonged survival compared with anti-PD-L1 therapy alone. However, prolonged combined treatment resulted in tumor resistance to immunotherapy and increased expression of PD-L1, IDO1, HVEM, and Gal-9. Interestingly, after initial anti-PD-L1 monotherapy, dual TGFß and PD-L1 blockade promoted both immune evasion gene expression and tumor growth compared with that in tumors treated with continuous PD-L1 monotherapy. Alternatively, treatment with JAK1/2 inhibitor following initial anti-PD-L1 therapy effectively suppressed tumor growth and downregulated immune evasion gene expression in tumors, indicating the involvement of IFNγ signaling in immunotherapy resistance development. These results demonstrate an unappreciated effect of TGFß on the development of IFNγ-mediated tumor resistance to immunotherapy. SIGNIFICANCE: Blocking TGFß facilitates IFNγ-mediated resistance to anti-PD-L1 therapy due to the role of TGFß in inhibiting IFNγ-induced immunoevasion by increasing SHP1 phosphatase activity in tumor cells.

Halide perovskite photoelectric artificial synapses: materials, devices, and applications.

In recent years, there has been a research boom on halide perovskites (HPs) whose outstanding performance in photovoltaic and optoelectronic fields is obvious to all. In particular, HP materials find application in the development of artificial synapses. HP-based synapses have great potential for artificial neuromorphic systems, which is due to their outstanding optoelectronic properties, femtojoule-level energy consumption, and simple fabrication process. In this review, we present the physical properties of HPs and describe two types of synaptic devices including two-terminal (2T) memristors and three-terminal (3T) transistors. The HP layer in 2T memristors can realize the change in the device conductance through physical mechanisms dominated by ion migration. On the other hand, HPs in 3T transistors can be used as efficient light-absorbing layers and rely on some special device structures to provide reliable current changes. In the final section of the article, we discuss some of the existing applications of HP-based synapses and bottlenecks to be solved.

Nanoparticle-Mediated Targeted Drug Delivery to Remodel Tumor Microenvironment for Cancer Therapy.

Advanced research has revealed the crucial role of tumor microenvironment (TME) in tumorigenesis. TME consists of a complicated network with a variety of cell types including endothelial cells, pericytes, immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs) as well as the extracellular matrix (ECM). The TME-constituting cells interact with the cancerous cells through plenty of signaling mechanisms and pathways in a dynamical way, participating in tumor initiation, progression, metastasis, and response to therapies. Hence, TME is becoming an attractive therapeutic target in cancer treatment, exhibiting potential research interest and clinical benefits. Presently, the novel nanotechnology applied in TME regulation has made huge progress. The nanoparticles (NPs) can be designed as demand to precisely target TME components and to inhibit tumor progression through TME modulation. Moreover, nanotechnology-mediated drug delivery possesses many advantages including prolonged circulation time, enhanced bioavailability and decreased toxicity over traditional therapeutic modality. In this review, update information on TME remodeling through NPs-based targeted drug delivery strategies for anticancer therapy is summarized.

miR-301 regulates the SIRT1/SOX2 pathway via CPEB1 in the breast cancer progression.

Breast cancer, the most common malignant tumor in women, has become a worldwide burden for family and society. MicroRNAs (miRNAs or miRs) are recognized as critical mediators of cancer-related processes, since they have the ability to coordinately suppress multiple target genes. In this study, we aim to find out specific miRNAs involved in the progression of breast cancer and explore the underlying molecular mechanism. Bioinformatics analysis suggested miR-301 as a differentially overexpressed miRNA in breast cancer, which was confirmed by expression determination. Functional assays were employed to explore the effect of miR-301 and its downstream effectors cytoplasmic polyadenylation element-binding protein 1 (CPEB1), SIRT1, and SOX2 on malignant phenotypes of breast cancer. The interaction among these factors was explained using luciferase and RNA immunoprecipitation (RIP) assays. In addition, the in vivo impact of miR-301 on breast cancer was assessed by cellular tumorigenicity in nude mice. We found that miR-301 overexpression restricted CPEB1 level and further promoted cell proliferation, metastasis, and cell cycle progression and impeded apoptosis. Moreover, CPEB1 regulated breast cancer development by mediating the SIRT1/SOX2 pathway. Further, miR-301 overexpression accelerated tumor formation in nude mice. Our results indicate that miR-301 overexpression accelerates the progression of breast cancer through the CPEB1/SIRT1/SOX2 axis.

Erianin induces triple-negative breast cancer cells apoptosis by activating PI3K/Akt pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is a refractory subtype of breast cancer, 25-30% of which have dysregulation in the PI3K/AKT pathway. The present study investigated the anticancer effect of erianin on TNBC cell line and its underlying mechanism. METHODS: After treatment with erianin, MTT assay was employed to determine the MDA-MB-231 and EFM-192A cell proliferation, the nucleus morphological changes were observed by DAPI staining. The cell cycle and apoptotic proportion were detected by flow cytometry. Western blot was performed to determine the cell cycle and apoptosis-related protein expression and PI3K pathways. Finally, the antiproliferative activity of erianin was further confirmed by adding or not adding PI3K agonists SC79. RESULTS: Erianin inhibited the proliferation of MDA-MB-231 and EFM-192A cells in a dose-dependent manner, the IC50 were 70.96 and 78.58 nM, respectively. Erianin could cause cell cycle arrest at the G2/M phase, and the expressions of p21 and p27 were up-regulated, while the expressions of CDK1 and Cyclin B1 were down-regulated. Erianin also induced apoptosis via the mitochondrial pathway, with the up-regulation of the expression of Cyto C, PARP, Bax, active form of Caspase-3, and Caspase-9. Furthermore, p-PI3K and p-Akt expression were down-regulated by erianin. After co-incubation with SC79, the cell inhibition rate of erianin was decreased, which further confirmed that the attenuated PI3K/Akt pathway was relevant to the pro-apoptotic effect of erianin. CONCLUSIONS: Erianin can inhibit the proliferation of TNBC cells and induce cell cycle arrest and apoptosis, which may ascribe to the abolish the activation of the PI3K/Akt pathway.

Association between vitamin D receptor gene Cdx2 polymorphism and breast cancer susceptibility.

Vitamin D receptor (VDR) gene polymorphisms have been reported to influence susceptibility to breast cancer. However, published findings on the association between VDR Cdx2 polymorphism and breast cancer susceptibility are conflicting. To get a precise estimation of the association between VDR Cdx2 polymorphism and breast cancer susceptibility, we conducted a meta-analysis of four case-control studies with a total of 8,880 subjects (3,841 cases and 5,039 controls). The results showed that VDR Cdx2 polymorphism was not associated with risk of breast cancer (A versus G: OR = 0.96, 95% CI 0.84-1.09; AA versus GG: OR = 0.97, 95% CI 0.64-1.45; AA/GA versus GG: OR = 0.94, 95% CI 0.80-1.10; AA versus GG/GA: OR = 0.99, 95% CI 0.65-1.51). Subgroup analysis in Caucasians also showed that VDR Cdx2 polymorphism was not associated with risk of breast cancer in Caucasians. However, there was a significant association in Africans (A versus G: OR = 0.75, 95% CI 0.60-0.94; AA versus GG: OR = 0.53, 95% CI 0.29-0.99; AA/GA versus GG: OR = 0.75, 95% CI 0.57-0.97). Therefore, the association between VDR Cdx2 polymorphism and breast cancer susceptibility is only found in Africans. More studies are needed to further assess the association in Asians or Africans.