Lung cancer (LC) remains the leading cause of mortality from malignant tumors worldwide. Currently, a lack of serological biomarkers for early LC diagnosis is a major roadblock for early intervention and prevention of LC. To undertake this challenge, we employed a two-phase strategy to discover and validate a biomarker panel using a protein array-based approach. In Phase I, we obtained serological autoimmune profiles of 80 LC patients and 20 healthy subjects on HuProt arrays, and identified 170 candidate proteins significantly associated with LC. In Phase II, we constructed a LC focused array with the 170 proteins, and profiled a large cohort, comprised of 352 LC patients, 93 healthy individuals, and 101 patients with lung benign lesions (LBL). The comparison of autoimmune profiles between the early stage LC and the combined group of healthy and LBL allowed us to identify and validate a biomarker panel of p53, HRas, and ETHE1 for diagnosis of early stage LC with 50% sensitivity at >90% specificity. Finally, the performance of this biomarker panel was confirmed in ELISA tests. In summary, this study represents one of the most comprehensive proteome-wide surveys with one of the largest (i.e. 1,101 unique samples) and most diverse (i.e. nine disease groups) cohorts, resulting in a biomarker panel with good performance.
Purpose: Circulating microRNAs (miRNAs) have shown the potential for non-invasive diagnosis of various types of malignancies at an early stage. The aim of the study was to explore the feasibility of a combination of 8 serum miRNAs related to non-small-cell lung cancer (NSCLC) with the corresponding serum exosomal miRNAs in early diagnosis for the patients with NSCLC. Methods: We measured 8 serum miRNAs and the corresponding serum exosomal miRNAs including miR-21-5p, miR-126-3p, miR-141-3p, miR-146a-5p, miR-155-5p, miR-222-3p, miR-223-3p, and miR-486-5p in 48 patients with early NSCLC at stages I/II, 32 patients with lung benign lesion (LBL), and 48 healthy control (HC) by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The expression levels of 4 serum miRNAs including miR-21-5p, miR-141-3p, miR-222-3p, and miR-486-5p, and 2 serum exosomal miRNAs including miR-146a-5p and miR-486-5p in the early NSCLC group were significantly different from that in the LBL group and the HC group (P < 0.01). The areas under the receiver operating characteristic curves (AUC) of the 4 serum miRNAs and 2 serum exosomal miRNAs in the early NSCLC group were ≥0.697, of which serum exosomal miR-146a-5p and miR-486-5p were 0.813 and 0.886, respectively, and higher than that of the 4 serum miRNAs. Additionally, a combination of 4 serum miRNAs with 2 serum exosomal miRNAs improved the AUC to 0.960 for the patients with NSCLC at early stages, with a sensitivity of 85.42% and a specificity of 92.50%. Conclusion: This study suggests that serum exosomal miRNAs other than serum miRNAs might be preferable biomarkers for the patients with NSCLC at early stages, and a combination of serum miRNAs with serum exosomal miRNAs contributes to the further improvement of early diagnosis for NSCLC.
We performed transcriptome sequencing for hepatocellular carcinoma (HCC) and adjacent non-tumorous tissues to investigate the molecular basis of HCC. Nine HCC patients were recruited and differentially expressed genes (DEGs) were identified. Candidate fusion transcripts were also identified. A total of 1943 DEGs were detected, including 690 up-regulated and 1253 down-regulated genes, and enriched in ten pathways including cell cycle, DNA replication, p53, complement and coagulation cascades, etc. Seven candidate fusion genes were detected and CRYL1-IFT88 was successfully validated in the discovery sequencing sample and another 5 tumor samples with the recurrent rate of about 9.52% (6/63). The full length of CRYL1-IFT88 was obtained by 3′ and 5′ RACE. The function of the fusion transcript is closed to CRYL1 because it contained most of domain of CRYL1. According to the bioinformatics analysis, IFT88, reported as a tumor suppressor, might be seriously depressed in the tumor cell with this fusion because the transcript structure of IFT88 was totally changed. The function depression of IFT88 caused by gene fusion CRYL1-IFT88 might be associated with tumorigenesis or development of HCC.
Poorly differentiated (PD) hepatocellular carcinoma (HCC) has a worse prognosis compared to moderately differentiated (MD) and well differentiated (WD) HCC. We aimed to identify differentially expressed genes (DEGs) to explore the mechanism of PD HCC. Transcriptome sequencing was performed on tumor and adjacent non-tumorous tissues of PD, MD and WD HCC patients (3 for each group). DEGs were thus identified and functionally analyzed. Further RT-PCR was performed to validate DEGs specific for PD HCC in 47 pairs of samples (15 for PD, 18 for MD, 14 for WD). A total of 681 PD DEGs were detected, including 368 up-regulated and 313 down-regulated genes. Less DEGs were found for MD and especially for WD HCC. Through bioinformatics analysis, PD HCC DEGs were enriched in liver tissue and liver cancer cells, and in biological process and pathway including metabolism, cell cycle, translation and blood coagulation. Potential drugs and genetic perturbations were found to reverse the cancer condition. The RT-PCR results showed consistency with RNA-seq in the validation of 4 DEGs specific for PD HCC. This study detected and validated DEGs of PD HCC, which provides useful information on molecular mechanism of PD HCC for development of new biomarkers, therapeutic targets and drugs.
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