Circ_0006949 as a potential non-invasive diagnosis biomarker promotes the proliferation of NSCLC cells via miR-4673/GLUL axis.

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ_0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ_0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ_0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening.

CYB561 promotes HER2+ breast cancer proliferation by inhibiting H2AFY degradation.

Breast cancer (BRCA) has a high incidence and mortality rate among women. Different molecular subtypes of breast cancer have different prognoses and require personalized therapies. It is imperative to find novel therapeutic targets for different molecular subtypes of BRCA. Here, we demonstrated for the first time that Cytochromeb561 (CYB561) is highly expressed in BRCA and correlates with poor prognosis, especially in HER2-positive BRCA. Overexpression of CYB561 could upregulate macroH2A (H2AFY) expression in HER2-positive BRCA cells through inhibition of H2AFY ubiquitination, and high expression of CYB561 in HER2-positive BRCA cells could promote the proliferation and migration of cells. Furthermore, we have demonstrated that CYB561 regulates H2AFY expression, thereby influencing the expression of NF-κB, a downstream molecule of H2AFY. These findings have been validated through in vivo experiments. In conclusion, we propose that CYB561 may represent a novel therapeutic target for the treatment of HER2-positive BRCA. Graphical abstract CYB561 promotes the proliferation of HER2+ BRCA cells: CYB561 enhances the expression of H2AFY by inhibiting its ubiquitination, which leads to an increase expression of NF-κB in the nucleus. H2AFY, together with NF-κB, promotes the proliferation of HER2+ BRCA cells.

ZNF133 is a potent suppressor in breast carcinogenesis through dampening L1CAM, a driver for tumor progression.

Due to the complexity and heterogeneity of breast cancer, the therapeutic effects of breast cancer treatment vary between subtypes. Breast cancer subtypes are classified based on the presence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2. Thus, novel, comprehensive, and precise molecular indicators in breast carcinogenesis are urgently needed. Here, we report that ZNF133, a zinc-finger protein, is negatively associated with poor survival and advanced pathological staging of breast carcinomas. Moreover, ZNF133 is a transcription repressor physically associated with the KAP1 complex. It transcriptionally represses a cohort of genes, including L1CAM, that are critically involved in cell proliferation and motility. We also demonstrate that the ZNF133/KAP1 complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo by dampening the transcription of L1CAM. Taken together, the findings of our study confirm the value of ZNF133 and L1CAM levels in the diagnosis and prognosis of breast cancer, contribute to a deeper understanding of the regulation mechanism of ZNF133 for the first time, and provide a new therapeutic strategy and precise intervention target for breast cancer.

High Expression of RAI14 in Triple-Negative Breast Cancer Participates in Immune Recruitment and Implies Poor Prognosis Through Bioinformatics Analyses.

Objective: The purpose of current research is to explore the function of retinoic acid-induced protein 14 (RAI14), being a reciprocal protein of carboxypeptidase N1 (CPN1), and as a biomarker for prognosis and immunoregulatory effects in breast cancers. Methods: Interacting proteins of CPN1 were characterized by co-immunoprecipitation (CO-IP) and mass spectrometry. We evaluated RAI14 expression and related clinical prognosis based on bioinformatics methods. The level of relevance between RAI14 and infiltrating immune cells biomarkers was investigated by using TIMER and certificated by immunohistochemical staining and cytology experiments. Results: RAI14 is an interacting protein of CPN1. Higher RAI14 expression in TNBC was significantly correlated with poor prognosis in TNBC, especially (RFS: HR = 1.32, p = 0.015; DFS: HR = 1.18, p = 0.035). The estrogen receptor (ER), P53 status, and histological types and triple-negative status were observed and correlated with RAI14 expression. Moreover, the level of RAI14 was positive in relation with the expression of CD163 (M2 macrophages marker, r = 0.393, p = 1.89e-06) and PD-1 (T-cell exhaustion marker, r = 0.626, p = 4.82e-03), indicating RAI14 levels were mainly related to M2 macrophages and T-cell exhaustion infiltration in TNBC. Furthermore, CPN1 overexpression was accompanied by RAI14 and PD-L1 upregulation, and a correlation was found among them. Conclusions: RAI14 is a potential downstream molecule of CPN1, which may be a potential prognostic biomarker and identification of an immunosuppressive tumor microenvironment in TNBC.

Carboxypeptidase N1 is anticipated to be a synergy metrics for chemotherapy effectiveness and prognostic significance in invasive breast cancer.

BACKGROUND: The incidence and mortality of invasive breast cancer (IBC) are increasing annually. Hence, it is urgently needed to determine reliable biomarkers for not only monitoring curative effects, but evaluating prognosis. In present study, we aim to determine the potential role of Carboxypeptidase N1 (CPN1) in IBC tissues on chemotherapeutic efficacy and poor prognosis. METHODS: The expression level of CPN1 in IBC tissue samples (n = 123) was quantified by tissue microarray technique and immunohistochemical staining. Moreover, sera of IBC patients (n = 34) that underwent three to five consecutive chemotherapy sessions were collected. The patients were randomly stratified into a training (n = 15) as well as a validation group (n = 19). The expression of serum CA153 and CPN1 was quantified by electrochemiluminescence and ELISA assay, respectively. RESULTS: By univariate and multivariate Cox regression analysis, we show that CPN1 expression in IBC tissues, as an independent risk factor, is related to a poor overall survival (OS) and progression-free survival (PFS) (P < 0.05). Analysis of the data revealed that CPN1 over-expression could be consistently linked to adverse clinicopathological features such as lymph node metastasis and the pathological stage (pTNM) (P < 0.05). The serum CPN1 level trajectory of individual patients generally decreased during chemotherapy. In line with these findings were changes in the follow-up ultrasonography and a consistent decrease in serum CPN1 levels. The comparison of the area under the receiver operating curves (ROC) revealed that CPN1 has a better surveillance value than CA153 in the training (AUCCPN1 = 0.834 vs. AUCCA153 = 0.724) as well as the validation set (AUCCPN1 = 0.860 vs. AUCCA153 = 0.720) when comparing cycle2 versus cycle3. CONCLUSIONS: CPN1 is a suitable potential biomarker for chemotherapeutic surveillance purposes as well as being an appropriate prognostic indicator which would support an improved chemotherapy regimen.