Issue 2 (June)

The latent transforming growth factor-beta (TGF-β) binding protein 1 (LTBP1) has been implicated in various cellular processes, but its role in triple-negative breast cancer (TNBC) remains unclear. In this study, we investigated the impact of LTBP1 on TNBC progression and its underlying mechanisms. Analysis of online datasets revealed elevated LTBP1 mRNA expression in breast cancer tissues compared to normal adjacent tissues. Kaplan-Meier Plotter analysis indicated that high LTBP1 expression was negatively correlated with relapse-free survival (RFS), distant-metastasis free survival (DMFS), and overall survival (OS) of breast cancer patients. Additionally, LTBP1 mRNA levels were associated with chemotherapy resistance. Functional assays in TNBC cells demonstrated that LTBP1 knockdown suppressed cell proliferation, induced apoptosis, and attenuated migration and invasion. In vivo studies confirmed that LTBP1 knockdown inhibited tumor growth in a xenograft mouse model. Mechanistically, LTBP1 positively correlated with genes involved in signaling regulation and organelle organization, with significant associations to GTPase binding and the RhoA/ROCK pathway. LTBP1 knockdown reduced RhoA activity and phosphorylation of Myosin Light Chain 2 (MLC2), suggesting inhibition of the RhoA/ROCK signaling pathway. Moreover, activation of the RhoA/ROCK pathway partially rescued the effects of LTBP1 knockdown on TNBC cell proliferation, apoptosis, migration, and invasion. In conclusion, our findings suggest that LTBP1 promotes TNBC progression through activation of the RhoA/ROCK signaling pathway, highlighting its potential as a therapeutic target for TNBC.

Background: Bladder cancer (BLCA), particularly invasive BLCA, has become a medical burden worldwide as it is associated with recurrence and easy metastasis. There are specific differences in the expression of various miRNAs in tumor and normal tissues. Hence, miRNAs can be used as biomarkers for tumor diagnosis and prognostic evaluation. The current study aimed to predict the downstream target genes of BLCA-related miRNAs and explore their association with immune infiltration. Method: Data on BLCA-related mRNA and miRNA expression levels were downloaded from The Cancer Genome Atlas. Correlation analysis and Cox regression analysis were performed to validate the miRNA risk model. The infiltration of various immune cells should be compared to determine the distinct differences between the immunological microenvironment of the two risk groups. Results: A predictive framework of BLCA was established using the expression levels of two miRNAs. Cox regression analysis showed that the low-risk group had a better prognosis. Then, the target genes of miRNA were predicted, and the target genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Moreover, variations in immune cells and functions between the high- and low-risk groups were assessed. Conclusion: The prognostic features composed of two associated miRNAs (MIR-25, MIR-548AN) may help predict the overall survival of BLCA.

Background: Hepatocellular carcinoma (HCC) stands out as one of the most lethal cancers globally, given its complexity, recurrence following surgical resection, metastatic potential, and inherent heterogeneity. In recent years, researchers have systematically elucidated the significance of long non-coding RNA (lncRNA) in the initiation and progression of HCC. The introduction of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases has significantly enhanced the prognostic assessment of HCC. However, the association between HCC and cell senescence has been infrequently explored in the literature. Method: We downloaded liver hepatocellular carcinoma (LIHC)-related messenger RNA and lncRNA expression levels from TCGA. Correlation analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) regression analysis were employed to validate the lncRNA risk model associated with cellular aging. Comparing the infiltration of diverse immune cells enabled the identification of distinct differences in the immunological microenvironments of the two risk groups. Subsequently, we conducted a real-time polymerase chain reaction (qPCR) experiment to confirm the accuracy of the selected lncRNAs. Results: A predictive framework for HCC was constructed based on the expression levels of five lncRNAs. Multivariate and univariate Cox regression analyses revealed that lncRNA signatures associated with senescence were independently correlated with an increased risk of HCC. Additionally, the nomogram also provides a more refined and sensitive model. Further investigation into the variations in immune cells and functions between the high-risk and low-risk groups was conducted. Subsequently, a qPCR experiment results revealed underexpression of AC068756.1, AC090578.1, AC145343.1, and LINC0022 in Huh7 and LM3 cells. In contrast, AP003392.4 did not exhibit a significant difference between Huh7 and control cells. Conclusion: The prognostic features and nomogram, consisting of five aging-related lncRNAs (AC068756.1, AC090578.1, AC145343.1, AP003392.4, and LINC00221), may be useful in predicting the overall survival of HCC.

Adenosine alterations to RNA, which are largely determined by RNA modification writers (RMWs), are critical for cancer growth and progression. These RMWs can catalyze different types of adenosine modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing. These modifications have profound effects on gene expression and function, such as immune response, cell development. Despite this, the clinical effects of RMW interactive genes on these cancers remain largely unclear. A comprehensive analysis of the clinical impact of these epigenetic regulators in pan-cancer requires further comprehensive exploration. Here, we systematically profiled the molecular and clinical characteristics of 26 RMWs across 33 cancer types using multi-omics datasets and validated the expression level of some RMWs in various cancer lines. Our findings indicated that a majority of RMWs exhibited high expression in diverse cancer types, and this expression was found to be significantly associated with poor patient outcomes. In the genetic alterations, the amplification and mutation of RMWs were the dominant alteration events. Consequently, the RNA Modification Writer Score (RMW score) was established as a means to assess the risk of RMWs in pan-cancer. We found that 27 of 33 cancers had significantly higher scores compared with normal tissues, and it was significantly correlated with prognosis. We also evaluated their impact on the tumor microenvironment and the response to immunotherapy and targeted therapy. These findings verified the important role of RMWs in different aspects of cancer biology, and provided biomarkers and personalized therapeutic targets for cancer.

Protein S-nitrosylation (SNO), emerging as an important posttranslational modification, involves covalent addition of nitric oxide (NO) to the sulfur atom of cysteine in proteins. Accumulated evidence suggests that protein SNO plays crucial roles in pathophysiological mechanisms in cancer, which is attracting great attention. However, there are still controversies about whether S-nitrosylated proteins act as oncogenic proteins or tumor suppressors in cancer. In this review, we provide an overview of the early and latest evidence regarding the underlying mechanism and dual roles of SNO in cancer, in an effort to clarify its contribution in tumor progression. It has been well established that S-nitrosylated proteins restrain tumor progression in several types of cancer, while they have exhibited activities in promoting cell proliferation and inhibiting apoptosis in some other kinds of cancer. Interestingly, emerging evidence also has highlighted both its anti-cancer and pro-tumorigenic roles in several other cancer diseases. Finally, current limitations and future research prospects are presented. The overview of targeting SNO in cancer will provide new opportunities for drug development through in-depth exploration of SNO-mediated signaling pathways.

Breast cancer, as a malignant tumor with easy metastasis and poor prognosis, threatens the health of women around the world. Increasing studies have shown that the Bcl-2 family of apoptosis-related proteins is often expressed abnormally in breast cancer. The Bcl-2 homology 3 (BH3) mimetic peptide can bind and neutralize Bcl-2, preventing its binding to the apoptosis "effector" proteins Bak and Bax, thereby promoting the apoptosis process. However, there is a lack of effective intracellular delivery system for BH3 to exert its biological activity. Therefore, this study utilized an activatable supercharged polypeptide (ASCP) tumor-targeted delivery platform based on pH and protease response to achieve the targeted release of BH3 at the tumor site. Ultimately, intracellular delivery of BH3 was achieved and induced apoptosis of breast tumor cells, preventing the development of breast cancer.