Variation of peripheral blood-based biomarkers for response of anti-PD-1 immunotherapy in non-small-cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) are on the rise, but unfortunately, only a small percentage of patients benefit from them in the long term. Thus, it is crucial to identify biomarkers that can forecast the efficacy of immunotherapy. METHODS: We retrospectively studied 224 patients with NSCLC who underwent anti-PD-1 therapy. The role of biomarkers and clinical characteristics were assessed in a prognostic model. RESULTS: Only 14.3% of patients had both programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) outcomes, highlighting the need to investigate more available biomarkers. Our analysis found a correlation between histological PD-L1 TPS and hematological PD-1 expression. Analysis of hematological biomarkers revealed that elevated expression of CD4/CD8 and LYM% are positively associated with effective immunotherapy, while PD-1+ on T cells, NLR, and MLR have a negative impact. Moreover, high level of ΔCEA%, CYFRA21-1 and LDH may suggest ineffective ICIs. We also observed that disparate immunotherapy drugs didn't significantly impact prognosis. Lastly, by comparing squamous carcinoma and adenocarcinoma cohorts, ΔCEA%, CD3+PD-1+, CD4+PD-1+, and CD4/CD8 are more important in predicting the prognosis of adenocarcinoma patients, while age is more significant for squamous carcinoma patients. CONCLUSION: Our research has yielded encouraging results in identifying a correlation between immunotherapy's response and clinical characteristics, peripheral immune cell subsets, and biochemical and immunological biomarkers. The screened hematological detection panel could be used to forecast an NSCLC patient's response to anti-PD-1 immunotherapy with an accuracy rate of 76.3%, which could help customize suitable therapeutic decision-making.

FOXO1-regulated lncRNA CYP1B1-AS1 suppresses breast cancer cell proliferation by inhibiting neddylation.

PURPOSE: Overactivated neddylation is considered to be a common event in cancer. Long non-coding RNAs (lncRNAs) can regulate cancer development by mediating post-translational modifications. However, the role of lncRNA in neddylation modification remains unclear. METHODS: LncRNA cytochrome P450 family 1 subfamily B member 1 antisense RNA 1 (CYP1B1-AS1) expression in breast cancer tissues was evaluated by RT-PCR and TCGA BRCA data. Gain and loss of function experiments were performed to explore the role of CYP1B1-AS1 in breast cancer cell proliferation and apoptosis in vitro and in vivo. Luciferase assay, CHIP-qPCR assay, transcriptome sequencing, RNA-pulldown assay, mass spectrometry, RIP-PCR and Western blot were used to investigate the regulatory factors of CYP1B1-AS1 expression and the molecular mechanism of CYP1B1-AS1 involved in neddylation modification. RESULTS: We found that CYP1B1-AS1 was down-regulated in breast cancer tissues and correlated with prognosis. In vivo and in vitro functional experiments confirmed that CYP1B1-AS1 inhibited cell proliferation and induced apoptosis. Mechanistically, CYP1B1-AS1 was regulated by the transcription factor, forkhead box O1 (FOXO1), and could be upregulated by inhibiting the PI3K/FOXO1 pathway. Moreover, CYP1B1-AS1 bound directly to NEDD8 activating enzyme E1 subunit 1 (NAE1) to regulate protein neddylation. CONCLUSION: This study reports for the first time that CYP1B1-AS1 inhibits protein neddylation to affect breast cancer cell proliferation, which provides a new strategy for the treatment of breast cancer by lncRNA targeting neddylation modification.

Long non-coding RNA MIR200CHG promotes breast cancer proliferation, invasion, and drug resistance by interacting with and stabilizing YB-1.

Long non-coding RNAs (lncRNA) have been identified as key regulators of tumorigenesis and development. We aim to explore the biological functions and molecular mechanisms of lncRNA MIR200CHG in breast cancer. We found that MIR200CHG is highly expressed in breast cancer tissues and is related to the tumor size and histopathological grade. In vitro and in vivo experiments confirmed that MIR200CHG can promote breast cancer proliferation, invasion, and drug resistance. MIR200CHG directly binds to the transcription factor Y-box binding protein-1 (YB-1), and inhibits its ubiquitination and degradation. MIR200CHG regulates YB-1 phosphorylation at serine 102, thereby affecting the expression of genes related to tumor cell proliferation, apoptosis, invasion, and drug resistance. Additionally, MIR200CHG partially affects the expression of miR-200c/141-3p encoded by its intron region. Therefore, MIR200CHG can promote the proliferation, invasion, and drug resistance of breast cancer by interacting with and stabilizing YB-1, and has the potential to become a target for breast cancer treatment.

tRNA-Derived Fragment tRF-17-79MP9PP Attenuates Cell Invasion and Migration via THBS1/TGF-ß1/Smad3 Axis in Breast Cancer.

tRNA derivatives have been identified as a new kind of potential biomarker for cancer. Previous studies have identified that there were 30 differentially expressed tRNAs derivatives in breast cancer tissue with the high-throughput sequencing technique. This study aimed to investigate the possible biological function and mechanism of tRNA derivatives in breast cancer cells. One such tRF, a 5'-tRF fragment of tRF-17-79MP9PP (tRF-17) was screened in this study, which is processed from the mature tRNA-Val-AAC and tRNA-Val-CAC. tRF-17 with significantly low expression in breast cancer tissues and serum. The level of tRF-17 differentiated breast cancer from healthy controls with sensitivity of 70.4% and specificity of 68.4%. Overexpression of tRF-17 suppressed cells malignant activity. THBS1 (Thrombospondin-1) as a downstream target of tRF-17, and reduction of THBS1 expression also partially recovered the effects of tRF-17 inhibition on breast cancer cell viability, invasion and migration. Besides, THBS1, TGF-ß1, Smad3, p-Smad3 and epithelial-to-mesenchymal transition related genes N-cadherin, MMP3, MMP9 were markedly down-regulated in tRF-17 overexpressing cells. Moreover, tRF-17 attenuated the THBS1-mediated TGF-ß1/Smad3 signaling pathway in breast cancer cells. In general, the tRF-17/THBS1/TGF-ß1/smad3 axis elucidates the molecular mechanism of breast cancer cells invasion and migration and could lead to a potential therapeutic target for breast cancer.

miR-219a-1 inhibits colon cancer cells proliferation and invasion by targeting MEMO1.

Colon cancer is the third most common cancer worldwide. Many miRNAs have been reported to be involved in colon cancer progression. However, there are only a few studies on the role of miR-219a-1 in colon cancer, and the molecular mechanisms involved remain unclear. The aim of this study was to investigate the miR-219a-1 level in patients with colon cancer and to explore both the effects and regulatory mechanisms of miR-219a-1 in the malignancy of colon cancer cells. Real-time PCR and western blot analysis were used to analyze the expression levels of miR-219a-1 and mediator of ErbB2-driven cell motility 1. Cell Counting Kit-8, transwell and wound-healing assays were performed to investigate the malignant ability of colon cancer cells. A luciferase assay was performed to explore whether miR-219a-1 could directly bind to 3'-UTR region of MEMO1. miR-219a-1 was found to be downregulated in colon cancer cell lines and in patients with colon cancer. Additionally, miR-219a-1 could inhibit colon cancer cell proliferation, invasion and migration. We identified MEMO1 as a novel potential target gene of miR-219a-1. Luciferase assays showed that miR-219a-1 could directly bind to 3'-UTR of MEMO1. Overexpression of miR-219a-1 in colon cancer cells could inhibit the expression of MEMO1. Furthermore, MEMO1 was upregulated in patients with colon cancer, which was inversely correlated with miR-219a-1 levels. In conclusion, our study revealed that miR-219a-1 exerts anti-tumor effects and regulates colon cancer cell proliferation, invasion and migration by targeting MEMO1, suggesting that miR-219a-1 could act as a therapeutic target in colon cancer.

DCST1-AS1 Promotes TGF-ß-Induced Epithelial-Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1.

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype, and the primary systemic treatment strategy involves conventional chemotherapy. DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long non-coding RNA that promotes TNBC migration and invasion. Studying the role of DCST1-AS1 in promoting epithelial-mesenchymal transition (EMT) and chemoresistance will provide a new strategy for TNBC therapy. In the present study, we found that DCST1-AS1 regulates the expression or secretion of EMT-related proteins E-cadherin, snail family zinc finger 1 (SNAI1), vimentin, matrix metallopeptidase 2 (MMP2), and matrix metallopeptidase 9 (MMP9). Interference with DCST1-AS1 impaired TGF-ß-induced TNBC cell invasion and migration. DCST1-AS1 directly binds to ANXA1 in BT-549 cells and affects the expression of ANXA1. DCST1-AS1 enhances TGF-ß/Smad signaling in BT-549 cells through ANXA1 to promote EMT. The combination of DCST1-AS1 and ANXA1 also contributes to enhancement of the resistance of BT-549 cells to doxorubicin and paclitaxel. In conclusion, DCST1-AS1 promotes TGF-ß-induced EMT and enhances chemoresistance in TNBC cells through ANXA1, and therefore represents a potentially promising target for metastatic breast cancer therapy.

A tRNA fragment, 5'-tiRNAVal, suppresses the Wnt/ß-catenin signaling pathway by targeting FZD3 in breast cancer.

tRNA-derived fragments offer a recently identified group of non-coding single-stranded RNAs that are often as abundant as microRNAs in cancer cells and play important roles in carcinogenesis. However, the biological functions of them in breast cancer are still unclear. Hence, we focused on investigating whether tiRNAs could play a key role in the progression of breast cancer. We have identified 5'-tiRNAVal with significantly low expression in breast cancer tissues. The down-regulation of serum 5'-tiRNAVal was positively correlated with stage progression and lymph node metastasis. Overexpression of 5'-tiRNAVal suppressed cells malignant activities. FZD3 was confirmed to be a direct target of 5'-tiRNAVal in breast cancer. In addition, FZD3, ß-Catenin, c-myc and cyclinD1 levels in 5'-tiRNAVal overexpressing cells were downregulated while APC was inversely upregulated. Moreover, 5'-tiRNAVal inhibited the FZD3-mediated Wnt/ß-Catenin signaling pathway in breast cancer cells. Finally, 5'-tiRNAVal levels differentiated breast cancer from healthy controls with a sensitivity of 90.0% and specificity of 62.7%. This is the first study to show that 5'-tiRNAVal as a new tumor-suppressor through inhibition of FZD3/Wnt/ß-Catenin signaling pathway, which could be as a potential diagnostic biomarker for breast cancer.

Serum Human Epididymis Secretory Protein 4 (HE4) is a Potential Prognostic Biomarker in Non-Small Cell Lung Cancer.

BACKGROUND: Human epididymis secretory protein 4 (HE4) is a secreted glycosylated protein belonging to the WFDC family, which is an ideal biomarker in ovarian cancer. However, the role of HE4 in lung cancer is still unclear. The study aimed to evaluate serum levels of HE4 as a prognostic biomarker in patients with non-small cell lung cancer (NSCLC). METHODS: The subjects consisted of 217 NSCLC patients, which were compared to a control group of 80 patients with benign lung disease and 110 healthy controls. Serum levels of HE4 were measured with electrochemiluminescence assays in a Roche E601 Immunoassay Analyzer. RESULTS: Serum levels of HE4 in NSCLC patients were significantly higher than in benign lung disease and healthy controls (p < 0.001). Using the cutoff value of 78.84 pmol/L, HE4 levels differentiated NSCLC from healthy controls with a sensitivity of 84.2% and a specificity of 78.3%. In the NSCLC subgroups, HE4 was a better discriminator of lung adenocarcinoma (cutoff value, 72.70 pmol/L, area under curve, 0.909; 95% confidence interval, 0.871 - 0.947). Higher serum HE4 levels were significantly correlated with histological type, high TNM stage, and positive lymph node metastasis (p = 0.019, 0.018, 0.002, respectively). Kaplan-Meier analysis demonstrated that high HE4 levels predicted poor survival (log-rank test: p = 0.007), especially in the adenocarcinoma group (logrank test: p = 0.001). In the Cox model, serum HE4 level was an independent prognostic factor for NSCLC. CONCLUSIONS: Higher serum levels of HE4 predict poor prognosis in NSCLC patients, especially in patients with adenocarcinoma.

miR-1290 promotes lung adenocarcinoma cell proliferation and invasion by targeting SOCS4.

miRNAs play important roles in lung adenocarcioma (LADC) progression. We previously found that miR-1290 expression was upregulated in LADC tissue and serum samples from patients with LADC, and correlated with prognosis. However, the biological role of miR-1290 in LADC and mechanism of such role are poorly understood. Here, we found that miR-1290 overexpression promoted LADC cell proliferation, cell cycle progression and invasion, while suppressing cell apoptosis in vitro. Furthermore, miR-1290 promoted tumor growth, invasion and metastasis in vivo. miR-1290 downregulated suppressor of cytokine signaling 4 (SOCS4) at both the mRNA and protein levels by targeting SOCS4. Reduced SOCS4 level reversed the inhibitory effect of miR-1290 downregulation on cell proliferation and invasion. miR-1290 activated the JAK/STAT3 and PI3K/AKT signaling pathways by targeting SOCS4. An inverse correlation was observed between miR-1290 and SOCS4 expression in LADC tissues. Clinicopathological characteristics analysis showed that SOCS4 expression was negatively associated with higher clinical stage and lymph node metastasis. These observations suggest that miR-1290 promotes LADC cell proliferation and invasion by targeting SOCS4.

MiRNA-145 suppresses lung adenocarcinoma cell invasion and migration by targeting N-cadherin.

OBJECTIVE: To investigate the roles of miR-145 in lung adenocarcinoma (LAC) and to clarify the regulation of N-cadherin by miR-145. RESULTS: In 57 paired clinical LAC tissues, diminished miR-145 was significantly correlated with the lymph node metastasis and was negatively correlated with N-cadherin mRNA level expression. Wound healing and transwell assays revealed a reduced capability of tumor metastasis induced by miR-145 in LAC. miR-145 negatively regulated the invasion of cell lines through targeting N-cadherin by directly binding to its 3'-untranslated region. Silencing of N-cadherin inhibited invasion and migration of LAC cell lines similar to miR-145 overexpression. CONCLUSIONS: MiR-145 could inhibit invasion and migration of lung adenocarcinoma cell lines by directly targeting N-cadherin.

miR-1290 is a potential prognostic biomarker in non-small cell lung cancer.

BACKGROUND: miR-1290 is a newly discovered microRNA (miRNA), and its role in non-small cell lung cancer (NSCLC) remains unknown. This study aimed to evaluate the expression levels of miR-1290 in NSCLC tissues and serum, and explore its associations with clinicopathological characteristics and prognosis of NSCLC patients. METHODS: A total of 33 pairs of tissues and 73 serum samples were obtained from NSCLC patients and expression levels of miR-1290 were detected by specific TaqMan qRT-PCR. The relationship between miR-1290 expression levels in NSCLC tissues and serum and clinicopathological characteristics was estimated respectively. The correlation between serum miR-1290 expression levels and overall survival of NSCLC patients was performed by Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: We determined that miR-1290 expression levels were increased significantly in NSCLC tissues compared with non-tumor adjacent normal tissues, and higher miR-1290 expression levels were positively correlated with high tumor stage (P=0.004) and positive lymph node metastasis (P=0.013). Compared with benign lung disease and healthy controls, serum levels of NSCLC patients exhibited higher expression of miR-1290. Furthermore, the up-regulation of serum miR-1290 more frequently occurred in NSCLC patients with high TNM stage, positive lymph node metastasis (P=0.022 and P=0.024, respectively). Kaplan-Meier analysis demonstrated that high serum miR-1290 expression levels predicted poor survival (P=0.022). Cox proportional hazards risk analysis indicated that miR-1290 was an independent prognostic factor for NSCLC. CONCLUSIONS: Our study suggests that miR-1290 is overexpressed in NSCLC, and serum miR-1290 may be used as a potential prognostic biomarker for NSCLC.

Joint effects of serum uric acid and body mass index on risk of prehypertension in Chinese population.

BACKGROUND: There are few data available on the association between serum uric acid (UA) and prehypertension when hypertension prevention efforts may be applicable. METHODS: We performed a cross-sectional study to evaluate risk of prehypertension and its association with serum UA and other confounding factors. Levels of serum UA, blood pressure, body mass index (BMI) and some related factors were detected. RESULTS: Participants with prehypertension had higher levels of serum UA and BMI. Compared to those with normotension, the multivariate-adjusted odds ratios [ORs, 95% confidence interval (CI)] for men with prehypertension were 1.33 (95% CI, 1.08-3.91) of serum UA and 1.21 (95% CI, 1.17-1.29) of BMI. In women, the ORs were 1.96 (95% CI, 1.21-3.46) and 1.28 (95% CI, 1.14-2.46), respectively. Increasing serum UA and BMI were associated with increased risk of prehypertension. Compared with the lowest quartiles, the highest serum UA and BMI quartiles entailed >4.4 times greater risk of prehypertension. In sex-specific analysis, OR was 2.41 (95% CI, 1.55-3.75) for men and 7.37 (95% CI, 4.16-13.0) for women. CONCLUSIONS: Both high serum UA and high BMI are associated with risk of prehypertension. Individuals with higher serum UA and BMI simultaneously have a higher risk for prehypertension, especially for women.

Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 promotes cell proliferation and migration by upregulating DNMT1 via STAT3 activation.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS), the most common AIDS-related malignancy. KSHV vIL-6 promotes KS development, but the exact mechanisms remain unclear. Here, we reported that KSHV vIL-6 enhanced the expression of DNA methyltransferase 1 (DNMT1) in endothelial cells,increased the global genomic DNA methylation, and promoted cell proliferation and migration. And this effect could be blocked by the DNA methyltransferase inhibitor, 5-azadeoxycytidine. We also showed that vIL-6 induced up-regulation of DNMT1 was dependent on STAT3 activation. Therefore, the present study suggests that vIL-6 plays a role in KS tumorigenesis partly by activating DNMT1 and inducing aberrant DNA methylation, and it might be a potential target for KS therapy.