At present, there is no effective noninvasive method for the accurate diagnosis of early-stage lung adenocarcinoma (LUAD). This study examined the profile of plasma extracellular vesicle (EV)-delivered microRNAs (miRNAs) in patients with invasive stage I LUAD. In this study, a total of 460 participants were enrolled, including 254 patients with LUAD, 76 patients with benign pulmonary nodules (BPNs), and 130 healthy control patients (HCs). miRNA sequencing was used to analyze the EV miRNA profile of the patient plasma samples (n = 150). A diagnostic signature (d-signature) was identified by applying a stepwise logistic regression algorithm, and a single-center training cohort (n = 150) was tested, followed by a multicenter validation cohort (n = 100). A d-signature comprising four EV-derived miRNAs (hsa-miR-106b-3p, hsa-miR-125a-5p, hsa-miR-3615, and hsa-miR-450b-5p) was developed for the early detection of LUAD. The d-signature had high precision with area under the curve (AUC) values of 0.917 and 0.902 in the training and test cohorts, respectively. Moreover, the d-signature could recognize patients with adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) with AUC values of 0.846 and 0.92, respectively. To sum up, our study detailed the plasma EV-derived miRNA profile in early LUAD patients and developed an EV-derived miRNA d-signature to detect early LUAD.

Small cell lung cancer (SCLC) is the most devastating subtype of lung cancer with no clinically available prognostic biomarkers. N6 -methyladenosine (m6 A) and noncoding RNAs play critical roles in cancer development and treatment response. However, little is known about m6 A-related long noncoding RNAs (lncRNAs) in SCLC. We used 206 limited-stage SCLC (LS-SCLC) samples from two cohorts to undertake the first and most comprehensive exploration of the m6 A-related lncRNA profile in SCLC and constructed a relevant prognostic signature. In total, 289 m6 A-related lncRNAs were screened out. We then built a seven-lncRNA-based signature in the training cohort with 48 RNA sequencing data using univariate and multivariate Cox regression models. The signature was well validated in an independent cohort containing 158 cases with quantitative PCR data. In both cohorts, the signature divided patients into high- and low-risk groups with significantly different survival rates (both p < 0.001). Our signature predicted chemotherapy survival benefit in patients with LS-SCLC. Receiver operating characteristic and C-index analyses indicated that the signature was better at predicting prognosis and chemotherapy benefit than other clinicopathologic features. Moreover, the signature was identified as an independent predictor of prognosis and chemotherapy response in different cohorts. Furthermore, functional analysis showed that multiple activated immune-related pathways were enriched in the low-risk group. Additionally, the signature was also closely related to various immune checkpoints and inflammatory responses. We generated the first clinically available m6 A-related lncRNA signature to predict prognosis and chemotherapy benefit in patients with LS-SCLC. Our findings could help optimize the clinical management of patients with LS-SCLC and inform future therapeutic targets for SCLC.

Emerging evidence has indicated that deregulation of long non-coding RNAs (lncRNAs) can contribute to the progression and metastasis of human cancer, including hepatocellular carcinoma (HCC). However, the roles of most lncRNAs in HCC remain largely unknown. Here we found a long noncoding RNA termed SchLAH (seven chromosome locus associated with HCC; also called BC035072) was generally downregulated in HCC. Low expression of SchLAH was significantly correlated with shorter overall survival of HCC patients. In vitro and in vivo assays indicated that overexpression of SchLAH inhibited the migration and lung metastasis of HCC cells. Knockdown of SchLAH by siRNA pool promoted the migration of HCC cells. RNA pull-down and RNA immunoprecipitation assays demonstrated SchLAH physically interacted with fused in sarcoma (FUS). PCR array analysis showed that RhoA and Rac1 were the downstream effector molecules of SchLAH during HCC metastasis. Knockdown of FUS rescued the mRNA levels of RhoA and Rac1 that were repressed by SchLAH. These results suggest that SchLAH may suppress the metastasis of HCC cells by interacting with FUS, which indicates potential of SchLAH for the prognosis and treatment of HCC.

Neoadjuvant immunotherapy has significantly changed the therapeutic approach for treating patients with surgically resectable non-small cell lung cancer (NSCLC). Here, peripheral blood inflammation-based biomarkers as well as previously less focused eosinophil fraction, modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) were systematically included to comprehensively analyze their potential in predicting neoadjuvant immunotherapy efficacy and prognosis. We enrolled 189 patients (94 in training and 95 in validation cohorts) with stage I-III B surgically resectable NSCLC treated with neoadjuvant immunotherapy from the National Cancer Center of China. Baseline and post-treatment eosinophils fraction, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), PNI, mGPS, and their changes were calculated and analyzed for correlation with neoadjuvant immunotherapy efficacy and prognosis. In patients in the major pathological response (MPR) group, the post-treatment eosinophil fraction was significantly high, and NLR, PLR, SII, and MLR were significantly lower compared to the non-MPR group in both the training and validation cohorts. The receiver operating characteristic curve showed that post-treatment, eosinophil fraction and SII and their changing were two of the most important factors. Univariate and multivariate logistic regression analyses showed that post-treatment eosinophil fraction, SII, mGPS, and ΔSII could independently predict MPR in patients treated with neoadjuvant immunotherapy. Survival analysis showed a significant correlation between high post-treatment NLR, PLR, SII, mGPS, and their changes in ΔNLR and ΔSII elevation with poor overall survival and event-free survival of patients. Our results suggest that inflammatory biomarkers could predict the patient's response to neoadjuvant immunotherapy and prognosis.

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II-mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple-negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple-negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT- and stem traits-associated proteins, and vice versa in non-triple-negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere-forming ability. Based on RNA-seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing-mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions -156 to +177. Collectively, our study not only demonstrated the tumor-promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

Dysregulation of long noncoding RNA SNHG17 is associated with the occurrence of several tumors; however, its role in esophageal squamous cell carcinoma (ESCC) remains obscure. The present study demonstrated that SNHG17 was upregulated in ESCC tissues and cell lines, induced by TGF-β1, and associated with poor survival. It is also involved in the epithelial-to-mesenchymal transition (EMT) process. The mechanism underlying SNHG17-regulated c-Myc was detected by RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. SNHG17 was found to directly regulate c-Myc transcription by binding to c-Jun protein and recruiting the complex to specific sequences of the c-Myc promoter region, thereby increasing its expression. Moreover, SNHG17 hyperactivation induced by TGF-β1 results in PI3K/AKT pathway activation, promoting cells EMT, forming a positive feedback loop. Furthermore, SNHG17 facilitated ESCC tumor growth in vivo. Overall, this study demonstrated that the SNHG17/c-Jun/c-Myc axis aggravates ESCC progression and EMT induction by TGF-β1 and may serve as a new therapeutic target for ESCC.

Lymphoid-specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.

Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p-ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p-ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara-C)-resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara-C treatment in both primary p-ALL cells and pre-B-ALL-driven leukemia xenografts and prolonged the survival of tumor-bearing mice. These data highlight an interconnected network of BACH2-FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara-C resistance in p-ALL.

Osteosarcoma (OS) is a primary and highly malignant mesenchymal tissue tumor. The specific pathological mechanism underlying disease initiation or progression remains unclear. Circular RNAs (circRNAs) are a type of covalently circular RNA with a head-to-tail junction site. In this study, we aimed to investigate the sponging mechanism between circRNAs and microRNAs (miRNAs) in OS. Based on the inhibited effect of miR-16-5p reported on OS, circUSP34 was analyzed as a sponge of miR-16-5p via Starbase. We found that circUSP34 promoted the proliferation, migration, and invasion of OS in vitro and in vivo. circUSP34 increased but miR-16-5p decreased in OS by qRT-PCR. Function assays showed that the malignancy of OS cells, including proliferation, migration, and invasion, was inhibited after knocking out circUSP34. Western blotting results showed that the expression level of vimentin and Ki-67 decreased. Similarly, miR-16-5p mimic compromised the proliferation, migration, and invasion of OS cells. FISH assay results indicated that circUSP34 and miR-16-5p were colocalized in the cytoplasm. The sponging mechanism of circUSP34 and miR-16-5p was verified by dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down assays. Interestingly, the miR-16-5p inhibitor partly reversed the inhibitory effect of sh-circUSP34 on the malignancy of OS cells. Further, mice tumors for IHC indicated that vimentin, N-cadherin, and Ki-67 protein expression decreased, but E-cadherin protein expression increased. Collectively, circUSP34 promoted OS malignancy, including proliferation, migration, and invasion, by sponging miR-16-5p. It can serve as a potential therapeutic target and biomarker.