circ-0000512 inhibits PD-L1 ubiquitination through sponging miR-622/CMTM6 axis to promote triple-negative breast cancer and immune escape.

BACKGROUND: This study reported the function and mechanism of circ-0000512 in the progression of triple-negative breast cancer (TNBC). METHODS: circ-0000512 expression in TNBC tissues and paired adjacent normal tissues and cells was examined by qRT-PCR. Moreover, circ-0000512 expression in TNBC cells was modulated by transfection. Thereafter, colony formation assay, Transwell assay and flow cytometry were conducted to observe cell proliferation, migration and apoptosis. TNBC cells were treated with cycloheximide and the protease inhibitor MG132. Later, ubiquitination assay was performed to detect programmed cell death ligand 1 (PD-L1) ubiquitination in TNBC cells. The T cell killing ability was assessed by the T cell-mediated tumor cell killing assay. IFNγ and IL-2 levels were detected by ELISA. The percentage of activated T cells was detected with a flow cytometer. In addition, dual luciferase reporter gene assay and RNA immunoprecipitation assay were carried out to evaluate the binding between two genes. In vivo study was conducted on mice. CD8+ T cells in xenograft tumors were detected by immunohistochemistry. RESULTS: circ-0000512 was upregulated in patients with TNBC. circ-0000512 knockdown attenuated the proliferation and migration of TNBC cells and enhanced their apoptosis. circ-0000512 overexpression had opposite effects. circ-0000512 knockdown enhanced the PD-L1 protein ubiquitination in TNBC cells by inhibiting CMTM6. Meanwhile, circ-0000512 promoted CMTM6 expression by sponging miR-622. circ-0000512 knockdown increased the ratio of CD8+T cells and the lethality of T cells against TNBC cells. Besides, circ-0000512 knockdown inhibited the growth of TNBC cells in immunodeficient nude mice and normal immune mice and increased the ratio of CD8+T cells in xenograft tumors of normal immune mice. CONCLUSIONS: circ-0000512 inhibited PD-L1 ubiquitination by sponging the miR-622/CMTM6 axis, thus promoting TNBC progression and immune escape.

Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway.

BACKGROUND/OBJECTIVES: Ribonucleotide Reductase M2 subunit (RRM2) is elevated in pancreatic cancer and involved in DNA synthesis and cell proliferation. But its specific mechanism including genetic differences and upstream regulatory pathways remains unclear. METHODS: We analyzed RRM2 expression of 178 pancreatic cancer patients in Gene Expression Profiling Interactive Analysis (GEPIA) database. Besides, more pancreatic cancer specimens were collected and detected RRM2 expression by immunohistochemistry. RRM2 knockdown by shRNA was applied for functional and mechanism analysis in vitro. Xenograft tumor growth was significantly slower by RRM2 silencing in vivo. RESULTS: It showed that high RRM2 expression had a poorer overall survival and disease free survival. RRM2 expression was higher in tumor grade 2 and 3 than grade 1. Immunohistochemistry data validated that high RRM2 expression predicted worse survival. RRM2 knockdown significantly reduced cell proliferation, inhibited colony formation and suppressed cell cycle progress. Further mechanism assay showed silencing RRM2 lead to inactivation of PI3K/AKT/mTOR pathway and inhibition of mutant p53, which induce S phase arrest and/or apoptosis. In panc-1 cells, S-phase arrest mediated by mutant p53 inhibition, p21 increase and cell cycle related proteins change. While in miapaca-2 cells, induction of apoptosis and S-phase arrest mediated by CDK1 played a coordinated role. CONCLUSION: Taken together, high RRM2 expression was associated with worse prognosis. Importantly, RRM2 knockdown deactivated PI3K/AKT/mTOR pathway, resulting in cell cycle arrest and/or apoptosis. This study shed light on the molecular mechanism of RRM2 in pancreatic tumor progression and is expected to provide a new theoretical basis for pancreatic cancer treatment.

Clinical Significance of TET2 in Female Cancers.

Female cancers refer to malignant tumors of the female reproductive system and breasts, which severely affect the physical and mental health of women. Although emerging experiment-based studies have indicated a potential correlation between ten-eleven translocation methylcytosine dioxygenase (TET2) and female cancers, no comprehensive studies have been conducted. Therefore, this study aimed to summarize the clinical value and underlying oncogenic functions of TET2 in female cancers, such as breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS), based on the data obtained from The Cancer Genome Atlas. The expression of TET2 was decreased in most female cancers, and its high expression was distinctly associated with the favorable prognosis of most female cancers. Furthermore, CD8+ T-cell infiltration was not correlated with TET2 in OV, UCEC, and UCS, whereas tumor-associated fibroblast infiltration was significantly correlated with TET2 in BRCA, CESC, and OV. TET2 was co-expressed with the immune checkpoint molecules ADORA2A, CD160, CD200, CD200R1, CD44, CD80, NRP1 TNFSF4, and TNFSF15 in most female cancers. Enrichment analysis revealed that some signaling pathways involving TET2 and related genes were related to tumorigenesis. Immunohistochemical and immunofluorescence staining confirmed the results of cancer immune infiltration analysis in BRCA tissues. Therefore, this study provides evidence for the oncogenic functions and clinical value of TET2 in female cancers.

Postoperative analgesic effect of parecoxib sodium local anesthesia in patients with breast cancer through systematic review and meta-analysis.

BACKGROUND: Postoperative pain can seriously affect a patient's recovery, and parecoxib sodium has a good analgesic effect. However, there is a lack of clinically systematic analyses of the effects of parecoxib sodium on postoperative pain in breast cancer patients. The aim of the present study was to systematically evaluate the efficacy and safety of parecoxib sodium local anesthesia in the treatment of postoperative pain in breast cancer patients. METHODS: Literature published from January 2010 to December 2020 was searched in the China National Knowledge Infrastructure database, Wanfang database, PubMed, and Cochrane Library. Literature on randomized controlled trials of parecoxib sodium local anesthesia in patients with breast cancer was collected. Method of treatment was extracted and literature quality was assessed. Meta-analyses of included literature were performed using RevMan 5.3. RESULTS: A total of 17 randomized controlled trials were included, with a total of 1,032 breast cancer surgery patients. The experimental group was treated with parecoxib sodium anesthesia, and the control group was treated with other anesthesia methods. The meta-analysis results showed that there were obvious differences among visual analogue scale (VAS) score of the experimental group and control group 2 h after surgery [mean difference (MD): -0.79; 95% confidence interval (CI): -1.29 to -0.29; P=0.002], 4 h (MD =-0.77; 95% CI: =-1.51 to -0.03; P=0.04), 6 h (MD: -1.10; 95% CI: -1.41 to -0.80; P<0.00001), 8 h (MD: -0.66; 95% CI: -1.00 to -0.33; P=0.0001), 12 h (MD: -0.92; 95% CI: -1.24 to -0.60; P<0.00001), 24 h (MD: -0.86; 95% CI: -1.15 to -0.58; P<0.00001), and 48 h (MD: -0.90; 95% CI: -1.47 to -0.33; P=0.002). Moreover, visual analog scale score and the postoperative controlled analgesia frequency of patients in the experimental group (MD: -2.08; 95% CI: -2.88 to -1.27; P<0.00001) and the incidence of adverse reactions (odds ratio: 0.52; 95% CI: 0.34-0.80; P=0.002) were significantly reduced. DISCUSSION: Parecoxib sodium local anesthesia for breast cancer patients has good postoperative analgesia and treatment safety.

LncRNA IGBP1-AS1/miR-24-1/ZIC3 loop regulates the proliferation and invasion ability in breast cancer.

BACKGROUND: Breast cancer (BC) is one of the malignant solid tumors with the highest morbidity in the world. Currently, the therapeutic outcome of different types of treatment can be unsatisfactory. Novel lncRNA biomarkers in BC remains to be further explored. METHODS: Different expression of lncRNAs among BC tissues and adjacent normal tissues were identified with microarray analyses. A series of in vivo and in vitro gain-of-function laboratory procedures were conducted to study the biological functions of IGBP1-AS1. The prognostic effects on IGBP1-AS1 survival were evaluated by using in situ hybridization and survival analysis. In addition, other experiments including RNA pull down analysis, RNA immunoprecipitation, luciferase reporter assays, and chromatin immunoprecipitation as well as validating assays conducted in vivo were applied to identify the target and regulatory mechanisms of IGBP1-AS1. RESULTS: Significant down-regulation of IGBP1-AS1 was discovered in the cell lines and tissues of BC. With respect to its biological function, overexpression of IGBP1-AS1 had inhibitory effects on the invasion and proliferation of BC cells in vivo as well as in vitro. Analysis of the samples obtained from BC patients indicated a positive effect of IGBP1-AS1 on survival outcomes. LncRNA IGBP1-AS1/miR-24-1/ZIC3 axis as a loop can regulate the proliferation and invasion of BC cells. CONCLUSIONS: IGBP1-AS1 could have inhibitory impact on the invasion and proliferation of BC and may serve as a promising biomarker for BC.

MiR-34b-5p inhibits cell proliferation, migration and invasion through targeting ARHGAP1 in breast cancer.

This study aim at investigating the function of microRNA (miR)-34b-5p in breast cancer prognosis and development. qRT-PCR was used for miR-34b-5p expression examination in breast cancer samples. CCK8, immunohistochemistry, scratch wound healing, transwell assays were performed for cell experiments. Subcutaneously implanted tumor model was carried out for animal experiment. Western blot was conducted for protein expression detection. Bioinformatics analysis was performed for exploring the underlying mechanism. MiR-34b-5p expression was down-regulated in breast cancer samples and cells, and miR-34d-5p could inhibit cell viability, migration and invasion also delay tumor growth in vivo. Low miR-34b-5p expression showed a bad prognosis of breast cancer patients. MiR-34b-5p functioned as a tumor suppressor by targeting ARHGAP1, and ARHGAP1 knockdown could reverse the effect of miR-34b-5p inhibitor on breast cancer cells. MiR-34b-5p exerts an anti-tumorigenesis role in breast cancer cells by targeting ARHGAP1, which is profitable for the breast cancer diagnosis and molecular treatment.

miR-146a-5p targets interleukin-1 receptor-associated kinase 1 to inhibit the growth, migration, and invasion of breast cancer cells.

MicroRNAs (miRNAs) are associated with the formation and progression of many types of cancers. In the present study, the aim was to elucidate the involvement of miR-146a-5p in the regulation of human breast cancer (BC) cell growth and invasion, as well as the mechanisms underlying its effects. Reverse transcription-quantitative polymerase chain reaction results revealed that miR-146a-5p was markedly downregulated in BC tissues relative to those of adjacent normal tissues. miR-146a-5p expression was also markedly downregulated in BC cells. Overexpression of miR-146a-5p significantly suppressed the proliferation, invasion and migration of BC MDA-MB-453 and MCF7 cells. Furthermore, the results indicated that miR-146a-5p downregulated the expression of interleukin-1 receptor-associated kinase 1 (IRAK1) by directly binding to its 3'-untranslated region in BC cells. Furthermore, IRAK1 expression was observed to be markedly upregulated and inversely correlated with miR-146a-5p expression in BC tissues. Mechanical studies indicated that restoring IRAK1 expression reversed the miR-146a-5p-induced inhibitory effects on proliferation and invasion of BC cells. In conclusion, miR-146a-5p may act as a tumor suppressor in BC by directly targeting IRAK1. These results highlighted the potential of miR-146a-5p as a novel therapeutic target for the treatment of BC.

LINC00461 promotes cell migration and invasion in breast cancer through miR-30a-5p/integrin ß3 axis.

Mounting evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated and implicated in the occurrence and development of a wide range of human malignancies. LINC00461, a novel cancer-related lncRNA, has been reported to be highly expressed and serve as oncogene in glioma; however, its biological role in breast cancer (BC) remains obscure. This study aimed to explore the role of LINC00461 in BC and elucidate the potential molecular mechanisms involved. In the current study, LINC00461 was found to be significantly upregulated in both BC tissues and cell lines. Besides, we found that high LINC00461 expression was associated with TNM stage and differentiation. Furthermore, functional studies demonstrated that LINC00461 expedited BC cell migration and invasion. Notably, LINC00461 was observed to enhance the expression of vimentin and zinc-finger E-box binding homeobox factor 1, suppress the expression of E-cadherin, and promote the activation of extracellular signal-regulated kinase and AKT signaling pathways. Mechanical investigations revealed that LINC00461 positively modulated integrin ß3 (ITGB3) expression as miR-30a-5p sponge in BC cells. Taken together, LINC00461 exerts an oncogenic role in BC through miR-30a-5p/ITGB3 axis. Our data indicate that LINC00461 may be used to be a novel candidate therapeutic target and a valuable diagnostic biomarker for BC.