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Simple Summary: tRF-27 has been identified as upregulated in both naïve trastuzumab-resistant HER2-positive breast cancer cells and patient samples, positioning it as a potential biomarker. However, the underlying mechanisms of this upregulation remain unclear. This study proposes that the abnormal transcription of specific tRNA-Cys-GCA isodecoders in naïve trastuzumab-resistant cells might contribute to the accumulation of tRF-27. Additionally, the reduction in H3K27me3 modifications at these tRNA genes, attributed to imbalances in histone modification enzymes, appears to influence tRNA transcription alterations. Building upon these findings, our research demonstrates that the application of a demethylase inhibitor may offer a potential strategy to overcome trastuzumab resistance. tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Palbociclib is one of the preferred treatments for hormone-receptor-positive, HER2-negative metastatic breast cancer in women; its effectiveness and safety in the Chinese real-world population require further investigation. Our study aimed to identify the clinical outcomes of patients who received palbociclib in combination with endocrine therapy (ET) in China. The effectiveness of palbociclib plus ET in treating metastatic breast cancer was confirmed in 397 Chinese patients across eight clinical sites. The regimens were well tolerated by both the general and elderly groups. However, some factors were identified as potential hindrances to the therapy's benefits, including higher Ki-67 expression, primary resistance to ETs, liver metastases, more metastatic sites, later line of therapy, and the use of fulvestrant instead of aromatase inhibitors. Palbociclib is useful for treatment of metastasis breast cancer, and our study may provide a basis for further research. Background: Palbociclib has been approved for marketing in China. However, its effectiveness, safety, and latent variables in the Chinese population require further investigation. Methods: Information was retrieved from 397 patients with metastatic breast cancer (mBC) who received at least two cycles of palbociclib plus endocrine therapy (PAL plus ET) at eight clinical sites in China. The patients' demographic characteristics, treatment patterns, and adverse events (AEs) were analyzed. Results: The objective response rate (ORR) and clinical benefit rate (CBR) for PAL plus ET were 28.97% and 66.25%, respectively. The median PFS was 14.2 months in the whole population. In addition to protein Ki-67 status and sensitivity to ETs, no liver metastases, fewer metastatic sites, an earlier line of therapy, and treatment combined with AI instead of FUL were also considered as independent prognostic factors for PAL treatment. Administration of PAL was generally well tolerated in patients with hormone-receptor-positive and human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) advanced breast cancer (ABC). The therapy was safe in the elderly population, which is consistent with the outcomes of the whole population and previous reports. Conclusions: In this most widely distributed study in China to date, palbociclib combined with ET proved its effectiveness for HR+/HER2− ABC treatment, and adverse events were manageable. Here, we identified some independent prognosis factors, but the mechanism by which these factors influence effectiveness requires further verification. [ABSTRACT FROM AUTHOR]

Simple Summary: While the prognosis of hormone receptor-positive (HR+) breast cancer has been significantly improved, tamoxifen resistance remains a challenge in the treatment of HR+ breast cancer. This study identified that tRF-16-K8J7K1B, a novel small ncRNA derived from the 3′-end of tRNAAla-TGC, was highly expressed in tamoxifen-resistant cells compared to parental cells. Moreover, extracellular tRF-16-K8J7K1B confers tamoxifen resistance via incorporation into exosomes and then degrades the expression of apoptosis-related proteins, reducing the proportion of drug-induced cell apoptosis. Therefore, we propose that exosomal tRF-16-K8J7K1B could be a potential predictive biomarker and therapeutic target for overcoming tamoxifen resistance. Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer. [ABSTRACT FROM AUTHOR]

tRNA‐derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA‐derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA‐derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA‐derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA‐derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA‐derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA‐derived fragments, the distinct expression and function of tRNA‐derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments. [ABSTRACT FROM AUTHOR]

Background: Amplification and overexpression of human epidermal growth factor receptor-2 (HER-2) has been shown in subgroups of gastric cancer, correlated to more aggressive disease and predictive for the treatment with HER-2 antibodies. In this study, we examined the prognostic value of HER-2 expression in primary gastric cancer and in associated lymph node metastases and confirmed the role of HER-2 in tumor angiogenesis by examining vascular endothelial growth factor (VEGF) expression. Methods: Immunohistochemistry was used to detect HER-2 and VEGF expression in 110 gastric cancer specimens and associated lymph node metastases and in 96 specimens of normal gastric mucosa. Results: The expression level of HER-2 in gastric tissues was significantly higher than in normal tissues (19.1 % vs. 8.3 %; P < 0.05). HER-2 overexpression was homogeneous in primary gastric cancer and metastatic lymph nodes ( P = 0.607). There was a significant positive correlation of HER-2 expression and VEGF expression ( P = 0.007). HER-2 overexpression in primary tumor correlated with lymph node metastasis, distant metastasis, and American Joint Committee on Cancer (AJCC) stage. Cox regression multivariate analyses confirmed that tumor size, histological grade, lymph node ratio, AJCC stage, chemotherapy, and HER-2 expression were all prognostic factors. Patients with HER-2 positivity in both primary and metastatic tissues (+/+) had the poorest survival (OS, 12.5 months; DFS, 11.0 months) ( P < 0.01). Conclusions: HER-2 was significantly overexpressed in gastric cancer versus normal tissue and correlated with VEGF expression. HER-2 in tumor or lymph nodes was an independent negative prognostic factor. [ABSTRACT FROM AUTHOR]

Genetic variants in human microRNA (miRNA) genes may alter mature miRNA processing and/or target selection, and likely contribute to cancer susceptibility and disease progression. Previous studies have suggested that miR-101 may play important roles in the development of cancer by regulating key tumor-associated genes. However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in breast cancer susceptibility remains unclear. In this study, we genotyped 11 SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study of 1064 breast cancer cases and 1073 cancer-free controls. The results revealed that rs462480 and rs1053872 in the flank regions of pre-miR-101-2 were significantly associated with increased risk of breast cancer (rs462480 AC/CC vs AA: adjusted OR = 1.182, 95% CI: 1.030–1.357, P = 0.017; rs1053872 CG/GG vs CC: adjusted OR = 1.179, 95% CI: 1.040–1.337, P = 0.010). However, the remaining 9 SNPs were not significantly associated with risk of breast cancer. Additionally, combined analysis of the two high-risk SNPs revealed that subjects carrying the variant genotypes of rs462480 and rs1053872 had increased risk of breast cancer in a dose-response manner (Ptrend = 0.002). Compared with individuals with “0–1” risk allele, those carrying “2–4” risk alleles had 1.29-fold risk of breast cancer. In conclusion, these findings suggested that the SNPs rs462480 and rs1053872 residing in miR-101-2 gene may have a solid impact on genetic susceptibility to breast cancer, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that underpin invasive ductal breast cancer (IDC) invasion and metastasis are incompletely understood. The oncogene, mouse double minute 2 (MDM2), has been implicated in the pathogenesis of numerous cancers, where it stimulates the expression of matrix metalloproteinase 9 (MMP9), an important enzyme in the breakdown of the extracellular matrix. However, its role in breast cancer remains poorly understood. This study assessed the clinical significance of MDM2 expression in IDC and used in vitro expression assays to determine the molecular roles of MDM2. Immunohistochemical staining for MMP9 and MDM2 was performed using archived tumor blocks from 321 women who underwent surgical resection for IDC at the First Affiliated Hospital of Nanjing Medical University, China between January 2002 and December 2003. MCF-7 and MDA-MD-231 cell lines were transfected with siRNA targeted against MDM2, or MDM2 was overexpressed using transiently expressed vectors. The invasion, cell migration and proteolytic capabilities of cells that over- or underexpressed MDM2 was then assessed and compared against control cells, in addition to the consequent effects on MMP9 expression using RT-PCR. In vivo, 54.9% and 49.6% of samples were positive for MMP9 and MDM2 expression, respectively, and their expression was significantly correlated (r2 = 0.171, P = 0.012). Moreover, MDM2 expression was markedly correlated with disease-free survival (HR 2.56, 95% CI 1.02–6.40, P = 0.038). In vitro, MDM2 overexpression significantly enhanced cell invasion, migration and proteolysis compared with control cells, and the converse effects were observed after MDM2-siRNA treatment. MDM2 overexpression induced MMP9 expression in a dose-dependent manner. Taken together, these results suggest that high levels of MDM2 are associated with a poorer prognosis in IDC. This might result from increased tumor invasiveness due to enhanced MMP9 expression causing increased extracellular matrix breakdown. [ABSTRACT FROM AUTHOR]

Both the deregulation of microRNAs and epidermal growth factor receptor ( EGFR) are emerging as important factors in non-small-cell lung cancer ( NSCLC). Here, miR-133b was found to be associated with tumor stage, the extent of regional lymph node involvement, stage, visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC. Bioinformatic analysis and luciferase reporter assay revealed that miR-133b can interact specifically with the 3′- UTR of EGFR mRNA. Functionally, miR-133b transfection showed regulatory activity in translationally repressing EGFR mRNA. Moreover, miR-133b transfection may modulate apoptosis, invasion and sensitivity to EGFR-TKI through the EGFR signaling pathways, especially in EGFR-addicted NSCLC cells. Taken together, our findings show that miR-133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway. This finding has important implications for the development of targeted therapeutics for a number of EGFR-addicted cancers. [ABSTRACT FROM AUTHOR]

Abstract: Vascular endothelial growth factor (VEGF) has been implicated in breast tumor angiogenesis. And tumor necrosis factor-α (TNF-α) is a positive regulator of VEGF. This study was aimed to identify the signalling pathway of TNF-α in VEGF expression regulation in breast cancer cell line MCF7. Using luciferase reporter assays, we demonstrated that TNF-α significantly increased activator protein-1 (AP-1) transcriptional activity in the MCF7 cells. The expression of the AP-1 family members c-Jun, c-Fos and JunB and phosphorylation levels of c-Jun were upregulated by TNF-α, whereas other AP-1 family members Fra-1, Fra-2, and JunD were unaffected. The activation of AP-1 was associated with the formation of p-c-Jun-c-Jun and p-c-Jun-JunB homodimers. Furthermore, the phosphorylation levels of c-Jun N-terminal kinase (JNK) but not P38 and ERK were elevated by TNF-α in MCF7 cells. TNF-α potently upregulated the mRNA and protein levels of VEGF, which were significantly reversed by JNK inhibitor SP600125. Finally using chromatin immunoprecipitation (CHIP) assays, we found that p-c-Jun bound to the VEGF promoter and regulated VEGF transcription directly. These data suggest that the pro-inflammatory cytokine TNF-α is a critical regulator of VEGF expression in breast cancer cells, at least partially via a JNK and AP-1 dependent pathway. [Copyright &y& Elsevier]

Abstract: Background and objectives: TNF-α secreted by tumor cells and macrophages that have infiltrated into the micro-environment of a tumor may promote the metastasis of a variety of malignant cancers, including breast cancer. The present study was designed to detect gene expression changes in metastatic MCF-7 cells treated with a low dose of TNF-α (20ng/mL), and to further explore the mechanisms by which TNF-α can contribute to metastasis. Methods: Transwell assays were performed to evaluate the invasive phenotype of MCF-7 cells. Samples for cDNA array analysis were collected 3h and 24h after pre-treatment with TNF-α and changes in gene expression were quantitated. Results: The invasive phenotype of MCF-7 cells was enhanced by the exposure of MCF-7 cells to a low dose of TNF-α. Gene expression profiles of 39 genes significantly increased or decreased after treatment with TNF-α, 6 of which were genes not previously associated with regulation by TNF-α. Genes to promote metastasis, as well as to inhibit metastasis, were identified with some changes being time dependent. Conclusions: TNF-α can enhance the invasive capacity of MCF-7 cells by affecting the expression of a group of genes that have roles in various steps of metastasis. Mechanistic insights into the role of TNF-α in tumor cell metastasis are discussed. [Copyright &y& Elsevier]

Abstract: Objective: Studies have shown that TNF-α secreted by tumor cells and macrophages infiltrated into the tumor microenvironment might promote the metastasis of a variety of malignant cancers, including breast cancer. The present study was designed to detect global metastasis-related gene expression changes of MCF-7 cells treated by low dose TNF-α and to further explore the mechanisms by which TNF-α contributes to metastasis. Methods: MCF-7 cells were cultured and treated with low dose TNF-α (20 ng/ml). cDNA array analysis was applied to detect the metastasis related gene expressions. Results: A total of 36 gene expressions were significantly regulated by TNF-α. Functional analysis indicates that the altered genes belong to different functional group. Most of the genes changed may promote the metastasis of MCF-7 cells while the others may inhibit metastasis. The changes observed in gene expression following TNF-α were somewhat time dependent. Conclusion: TNF-α can enhance the invasive ability of MCF-7 cells, partly by regulating a series of metastasis related genes, and these genes may take part in every step of metastasis. Some of the genes deserve further study. [Copyright &y& Elsevier]

Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), plays an essential role in tumor progression and metastasis, the expression of which on cell surface is a critical clinical testing index for cancer therapy. In this work, an electrochemical method to assay CD147/EMMPRIN expression on tumor cell surface is proposed. While the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) catalyzed by horseradish peroxidase (HRP) can be employed for electrochemical measurement, the signal enhancement amplified by gold nanoparticles (GNPs) can be also utilized in this study. Therefore, under optimized conditions, the fabricated biosensor responds linearly to the CD147/EMMPRIN concentration from 125 to 1000pg/mL with a detection limit as low as 52pg/mL. High sensitivity can also be achieved for the quantification of breast cancer cells in a linear range from 6.2×104 to 6.25×105 cells/mL. Moreover, the CD147/EMMPRIN expressed on a single breast cancer cell can be calculated as 2.57×104 molecules/cell. The proposed strategy in this study is considerably potential for monitoring the dynamic protein expression on cancer cells and for the effective cancer diagnosis and treatment in the future. [ABSTRACT FROM AUTHOR]

Abstract: We conducted this study to evaluate the expression of leptin and its receptor, OB-Rb in gastric cancer and their relationship to clinicopathological features, VEGF and HER-2 expression, as well as the prognostic value. One hundred and ten gastric cancer specimens were detected for leptin, OB-Rb, VEGF and HER-2 by immunohistochemistry (IHC), and 96 specimens of normal gastric mucosa served as the control. The expression level of leptin, OB-Rb and HER-2 in gastric tissues were significantly higher than normal tissues (49.1% vs. 34.0%, 60.9% vs. 46.0%, 19.1% vs. 8.0%, P <0.05). There was a correlation between the expression of leptin and HER-2, both of which were significantly associated with invasion depth, lymph node metastasis, AJCC stage and VEGF expression. However, there was no correlation between OB-Rb expression and all clinicopathological features. Cox regression analyses showed that age, tumor size, histological grade, serosa invasion, AJCC stage, chemotherapy, leptin and HER-2 overexpression were prognostic factors. The survival of patients with leptin positive expression was significantly poorer than those with negative expression (OS: 20.0months vs. 32.5months, FPS: 12.0months vs. 18.0months, P <0.01). Leptin, rather than OB-Rb, played an important role in the progression and angiogenesis of gastric cancer, and was a prognostic factor for poor outcome. [Copyright &y& Elsevier]