IFI30 as a key regulator of PDL1 immunotherapy prognosis in breast cancer.

BACKGROUND: IFI30 is a lysosomal thiol reductase involved in antigen presentation and immune regulation in various cancers, including breast cancer. Despite its known involvement, the precise mechanism, function, and relationship with the PD-L1 axis and immune response remain unclear. METHODS: We conducted an extensive investigation into IFI30 mRNA expression in breast cancer utilizing data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Furthermore, we characterized IFI30 mRNA expression across various cell types using publicly available single-cell RNA sequencing datasets, and assessed protein expression through immunohistochemistry using an in-house breast cancer tissue microarray. Functional experiments were performed to elucidate the effects of IFI30 overexpression on PD-L1 expression and inhibitory efficacy in both macrophages and breast tumor cells. RESULTS: Our study unveiled a marked upregulation of IFI30 expression in breast cancer tissues compared to their normal counterparts, with notable associations identified with tumor stage and prognosis. Additionally, IFI30 expression demonstrated significant correlations with various immune-related signaling pathways, encompassing peptide antigen binding, cytokine binding, and MHC class II presentation. Notably, breast cancer samples exhibiting high IFI30 expression in tumor cells displayed high PD-L1 expression on corresponding cells, alongside a diminished ratio of CD8 + T cell infiltration within the tumor microenvironment. Furthermore, ectopic knockdown of IFI30 in both tumor cells and macrophages resulted in a reduction of PD-L1 expression, while conversely, overexpression of IFI30 led to an increase in PD-L1 expression. CONCLUSIONS: This study offers new insights into the involvement of IFI30 in breast cancer, elucidating its interplay with the PD-L1 axis and immune response dynamics. Our findings suggest that modulation of the IFI30-PD-L1 axis could serve as a promising strategy for regulating T cells infiltration in breast cancer thus treating breast cancer.

Dosimetric comparison between intensity-modulated radiotherapy and volumetric-modulated arc therapy in patients of left-sided breast cancer treated with modified radical mastectomy: CONSORT.

ABSTRACT: Volumetric-modulated arc therapy (VMAT) is a novel treatment strategy that protects normal tissues and enhances target volume coverage during radiotherapy.This study aimed to clarify whether VMAT is superior to intensity-modulated radiotherapy (IMRT) in treatment planning for left-sided breast cancer patients after modified radical mastectomy.Left-sided breast cancer patients treated with modified radical mastectomy were eligible for analysis. The dose distribution of both planning target volume and organs at risk were analyzed by using dose volume histograms.Twenty-four patients were eligible for analysis. Both VMAT and IMRT plans were sufficient in planning target volume coverage. In terms of conformity, VMAT was superior to IMRT (P = .034). Dmean, V5, and V10 of the heart were significantly decreased in VMAT plans when compared with IMRT plans. VMAT was as effective as IMRT plans in sparing of other normal tissues. In addition, both the mean number of monitor units and treatment time were significantly reduced when VMAT was compared with IMRT.VMAT plans was equivalent or superior to IMRT plans in dose distribution, and was associated with slightly advantage in sparing of the heart and coronary arteries. Our analyses suggested VMAT as a preferred option in left-sided breast cancer patients treated with modified radical mastectomy.

LINC00922 regulates epithelial-mesenchymal transition, invasive and migratory capacities in breast cancer through promoting NKD2 methylation.

Breast cancer ranks as the major reason for mortality in women populations, accounting for 23% of all cancer deaths. One in every three Asian women encounters the risk of this cancer in their lifetime. Long intergenic non-coding RNAs (lincRNAs) have emerged as tumor promoters and suppressors. The molecular mechanism of breast cancer remains elusive. Therefore, the current study aimed to explore the role lincRNA LINC00922 plays in the development of breast cancer. Breast cancer tissues and adjacent tissues were obtained from 109 patients with breast cancer. The RNA extraction and quantification and immunohistochemical staining characterized the high expression of LINC00922 and low expression of NKD2 in breast cancer tissues in comparison to its adjacent counterparts. Furthermore, the ectopic expression and knockdown experiments were conducted to figure out the in vivo and in vitro effects of LINC00922 on breast cancer progression. The ectopically expressed LINC00922 activated the Wnt signaling pathway, promoted epithelial-mesenchymal transition, cell proliferative, invasive and migratory capacities, tumor growth and metastasis. Additionally, the RIP and ChIP assay identified that LINC00922 recruited DNMT1, DNMT3A and DNMT3B proteins in the promoter region of NKD2 to promote NKD2 promoter methylation, thus reducing the NKD2 expression. Moreover, the Wnt signaling pathway was activated subsequent to NKD2 silencing, which was reversed by LINC00922 silencing. Lastly, the anti-oncogenic effects of LINC00922 inhibition was antagonized after NKD2 knocked down. The current study provides evidence that LINC00922 acts as a tumor promoter by promoting NKD2 methylation. Hopefully, it provides a novel potential gene target for the treatment of breast cancer.

The Evolving Role of Disulfiram in Radiobiology and the Treatment of Breast Cancer.

Disulfiram (DSF), also known as "Antabuse", has been widely used in clinical practice to treat alcoholism. In the past decades, both in vivo and in vitro experiments showed that DSF has strong anti-cancer activity, there were some clinical studies indicated the administration of this drug was associated with favorable survival in breast cancer. It is also evident that DSF has a radioprotective effect on normal cells and could be utilized during the course of radiation therapy. Moreover, increasing evidences demonstrated the role of DSF in enhancing the radiosensitivity of tumor cells in number of alternative mechanisms. Recent studies have also elaborated the anticancer mechanism of DSF in tumor cells. This review summarizes the anticancer activity of DSF both in preclinical studies and clinical trials, focuses on the advances of this drug in radiobiology and the treatment of breast cancer, and reveals the promising of repurposing DSF as a novel radiosensitizer and radioprotector in further clinical trials.

Naringenin has a chemoprotective effect in MDA-MB-231 breast cancer cells via inhibition of caspase-3 and -9 activities.

Breast cancer is the leading cause of cancer-associated mortality in females. It has an incidence of 1.3 million per year, which increases by 2% annually. In China, breast cancer accounts for 12.2% of all cancer cases. The aim of the present study was to investigate the inhibitory effect of naringenin on triple-negative breast cancer cells. Lactate dehydrogenase and MTT assay was used to investigate the inhibitory effect of naringenin on MDA-MB-231 cell viability. Naringenin reduced the viability of MDA-MB-231 cells by arresting the cell cycle at the G2 phase. Naringenin treatment not only influenced the phase of cell cycle arrest, but also induced apoptosis in a dose-dependent manner. Naringenin treatment also resulted in a significant increase in caspase-3 and caspase-9 activity (P<0.001). Taken together, the results of the present study suggested that naringenin caused an inhibitory effect on MDA-MB-231 cells via induction of apoptosis and inhibition of caspase-3 and -9 activity.

Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture.

Cancer cells consume large amounts of glucose to produce lactate, even in the presence of ample oxygen. This phenomenon is known as the Warburg effect. The pyruvate kinase promotes aerobic glycolysis, and the pyruvate kinase M2 isoform (PKM2) is highly expressed in many cancer cells. Although the Warburg effect is a hallmark of cancer, the mechanism by which PKM2 contributes to the Warburg effect, and its role in tumor growth remain to be defined. We proposed that PKM2 activates transcription of hypoxia inducible factor-1α (HIF-1α) by phosphorylating STAT3 (signal transducer and activator of transcription 3) at Y705 (tyrosine 705) as a plausible mechanism for liver cancer cell proliferation. In the current study, we observed that PKM2 was over-expressed in hepatocellular carcinoma (HCC) tissues compared to adjacent normal tissues. The experiments further indicate that nuclear PKM2 is an active protein kinase in cultured cells. Knockdown of PKM2 affected the levels of HIF-1α and Bcl-xL (B-cell lymphoma-extra large), suggesting that PKM2 plays an important role in promoting cell proliferation. In conclusion, the current findings demonstrate that PKM2 is an active protein kinase, and promotes liver cancer cell proliferation by up-regulating HIF-1α and Bcl-xL expression.

Transplantation of ATP7B-transduced bone marrow mesenchymal stem cells decreases copper overload in rats.

BACKGROUND: Recent studies have demonstrated that transplantation of ATP7B-transduced hepatocytes ameliorates disease progression in LEC (Long-Evans Cinnamon) rats, a model of Wilson's disease (WD). However, the inability of transplanted cells to proliferate in a normal liver hampers long-term treatment. In the current study, we investigated whether transplantation of ATP7B-transduced bone marrow mesenchymal stem cells (BM-MSCs) could decrease copper overload in LEC rats. MATERIALS AND METHODS: The livers of LEC rats were preconditioned with radiation (RT) and/or ischemia-reperfusion (IRP) before portal vein infusion of ATP7B-transduced MSCs (MSCsATP7B). The volumes of MSCsATP7B or saline injected as controls were identical. The expression of ATP7B was analyzed by real-time quantitative polymerase chain reaction (RT-PCR) at 4, 12 and 24 weeks post-transplantation. MSCATP7B repopulation, liver copper concentrations, serum ceruloplasmin levels, and alanine transaminase (ALT) and aspartate transaminase (AST) levels were also analyzed at each time-point post-transplantation. RESULTS: IRP-plus-RT preconditioning was the most effective strategy for enhancing the engraftment and repopulation of transplanted MSCsATP7B. This strategy resulted in higher ATP7B expression and serum ceruloplasmin, and lower copper concentration in this doubly preconditioned group compared with the saline control group, the IRP group, and the RT group at all three time-points post-transplantation (p<0.05 for all). Moreover, 24 weeks post-transplantation, the levels of ALT and AST in the IRP group, the RT group, and the IRP-plus-RT group were all significantly decreased compared to those of the saline group (p<0.05 compared with the IRP group and RT group, p<0.01 compared with IRP-plus-RT group); ALT and AST levels were significantly lower in the IRP-plus-RT group compared to either the IRP group or the RT group (p<0.01 and p<0.05. respectively). CONCLUSIONS: These results demonstrate that transplantation of MSCsATP7B into IRP-plus-RT preconditioned LEC rats decreased copper overload and was associated with an increase in MSC engraftment and repopulation.

Transplantation of bone marrow-derived mesenchymal stem cells after regional hepatic irradiation ameliorates thioacetamide-induced liver fibrosis in rats.

BACKGROUND: Recent studies have demonstrated that bone marrow-derived mesenchymal stem cells (BM-MSCs) can potentially revert liver fibrosis, but it is not known if preparative hepatic irradiation (HIR) contributes to the therapeutic effect of transplanted BM-MSCs. In this study, we investigate the effects of HIR on transplanted BM-MSCs in cirrhotic rats and the underlying mechanism by which mesenchymal stem cells (MSCs) relieve liver fibrosis. MATERIALS AND METHODS: The BM-MSCs from male rats were labeled with CM-Dil and injected via portal vein into two groups of thioacetamide-induced cirrhotic rats, and the controls were injected with the same volume of saline. The right hemiliver of one cirrhotic rat group was irradiated (15 Gy) 4 d before transplantation. Liver function tests and histologic experiments were performed, and the liver population of BM-MSCs was estimated. RESULTS: The transplantation of MSCs alleviated liver fibrosis and reduced expression of transforming growth factor-ß1, Smad2, collagen type I, and α-SMA. HIR preconditioning promoted homing and repopulation of MSCs and resulted in better treatment outcomes. CONCLUSIONS: HIR preconditioning enhances the effect of BM-MSCs in improving thioacetamide-induced liver fibrosis in rats by promoting their homing and repopulation. BM-MSCs may function by inhibiting transforming growth factor-ß1-Smad signaling pathway in the liver.