Cancer Biomarkers

Early detection and diagnosis of lung cancer remain challenging but would improve patient prognosis. The goal of this study is to develop a model to estimate the risk of lung cancer for a given individual.

We conducted a case-control study to develop a predictive model to identify individuals at high risk for lung cancer. Clinical data from 500 lung cancer patients and 500 population-based age- and gender-matched controls were used to develop and evaluate the model. Associations between environmental variants together with single nucleotide polymorphisms (SNPs) of beta-catenin (ctnnb1) and lung cancer risk were analyzed using a logistic regression model. The predictive accuracy of the model was determined by calculating the area under the receiver operating characteristic (ROC) curve.

Prior diagnosis of chronic obstructive pulmonary disease (COPD), pulmonary tuberculosis, family history of cancer, and smoking are lung cancer risk factors. The area under the curve (AUC) was 0.740, and the sensitivity, specificity, and Youden index were 0.718, 0.660, and 0.378, respectively.

Our risk prediction model for lung cancer is useful for distinguishing high-risk individuals.

Baicalein is an important Chinese herbal medicine and has multiple pharmacological activities. However, the biological mechanisms of the anti-tumor effects of Baicalein on non small cell lung cancer (NSCLC) still need to be understood.

Human NSCLC A549 and H1299 cells were pretreated with Baicalein or DMSO. Cells viability and transwell cell invasion assays were performed to assess cell proliferation and invasion. QRT-PCR assay was used to analyze mRNA expression levels of Twist1, E-cadhertin, Vimentin, Notch1 and hes-1. Western blot analysis was also performed to determine protein expression.

In the study, we found that Baicalein had a significantly inhibited effect on proliferation ability of A549 and H1299 cells. Cells treated with Baicalein showed a down-regulated expression of CyclinD1 and CDK1 in A549 and H1299 cells. Furthermore, we found that Baicalein significantly inhibited cell invasion and Epithelial-Mesenchymal Transition (EMT) by up-regulating the mRNA and protein expression of E-cadherin and down-regulated the Twist1 and Vimentin expression, Moreover, Treatment of Baicalein down-regulated Notch1 and hes-1 expression in A549 and H1299 cells, which indicated that Baicalein could suppress the Notch signaling pathway.

Our studies suggest that Baicalein may be a potential phytochemical flavonoid for therapeutics of NSCLC and serve as a molecular target for NSCLC.

Prostate cancer (PCa) is the second most common cancer in men worldwide. Currently, prostate-specific antigen (PSA) test and digital rectal exam are the main screening tests used for PCa diagnosis. However, due to the low specificity of these tests, new alternative biomarkers such as deregulated RNAs and microRNAs have been implemented.

Aberrant expressions of small heterodimer partner gene (SHP, NR0B2) and mir-141 are reported in various cancers. The aim of this study was to investigate the SHP and miR-141 expression level in tissue samples of prostate cancer.

The expression level of SHP gene and miR-141 was assessed by real time PCR and their relative amounts were calculated by the Δ ⁢ Δ CT method. Also, IHC technique was used to determine the expression level of SHP protein.

The miR-141 was significantly up-regulated in the samples of metastatic tumors compared to localized tumor samples ( P < 0.001, 31.17-fold change). Tumor samples showed lower SHP mRNA expression levels than BPH samples ( p = 0.014, 4.7-fold change). The results of paired t -test analysis showed there was no significant difference between the SHP gene expression in PCa samples and their matched tumor-adjacent normal tissue ( p = 0.5).

The data obtained in our study confirm the involvement of miR-141 in PCa progression and metastasis. These effects could be mediated by AR via down-regulation of its co-repressor protein, i.e., SHP.

Cervical lymph node metastases (LNM) in papillary thyroid carcinomas (PTCs) are common and develop in approximately 30–80% of PTCs. The presence of cervical LNM significantly increases the rate of locoregional recurrence in PTCs.

To search for predictive gene signatures for nodal metastasis in PTCs.

We used unsupervised clustering with unbiased manner to compare molecular profiles between PTCs with nodal metastasis and PTCs without nodal metastasis using mRNA-seq of TCGA data. Using gene ontology (GO) and logistic regression test, we generated 12-predictive genes for nodal metastasis in PTCs.

Unsupervised clustering of mRNA-seq (training set, N = 158) revealed that PTCs with nodal metastasis showed different gene expression patterns compared to PTCs without nodal metastasis. We generated 12 predictive genes and these gene signatures showed consistency for predicting nodal metastasis when we applied them to a validation set (N = 80). Based on multivariate analysis, these 12 predictive gene signatures showed more significant odds ratio compared to other variables.

These 12 gene signatures could be used to predict the chance of nodal metastasis in PTCs in preoperative evaluation using fine needle aspiration biopsy (FNAB) so that appropriate plan such as central neck dissection could be made.

The neutrophil-to-lymphocyte ratio (NLR) at diagnosis has been identified as an independent prognostic marker in several malignancies. Recently, a few studies have reported that an elevated pretreatment NLR is associated with poor survival among multiple myeloma (MM) patients. However, the role of NLR at diagnosis in patients with MM treated with regimens containing bortezomib has been less explored.

We aimed to investigate the relationships between NLR and overall survival (OS) in newly diagnosed patients receiving bortezomib-based therapy for MM.

A total of 76 newly diagnosed patients with MM treated with bortezomib-based regimes were analyzed retrospectively. NLR was calculated from whole blood counts prior to therapy and subsequently correlated with OS.

Complete remission (CR) was seen in 39.2% of patients with NLR < 2.95 compared to 20% in the group with NLR ⩾ 2.95 ( P = 0.094). NLR was lower in CR patients in comparison to Non-CR subjects ( P = 0.044). Patients with a NLR ⩾ 2.95 experienced inferior median survival compared to those with NLR < 2.95 (4-year OS rates were 30.9% and 64.8%, respectively, P = 0.029). In multivariate analysis, only elevated LDH and IgA MM were factors predicting inferior OS.

Elevated NLR was associated with poor OS in MM patients receiving induction therapy with bortezomib-based regimens, but it was not an independent prognostic factor in this patient cohort.

Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) levels are prognostic predictors in non-small cell lung cancer (NSCLC). However, even in patients with the same stage of cancer, the serum levels of those markers often vary.

We investigated the association between the initial biomarker levels and prognosis.

We retrospectively reviewed 445 patients with advanced NSCLC and their baseline serum CEA and CYFRA 21-1 levels. Patients were divided into four groups according to the initial levels of those markers: the NN, HN, NH, and HH group. Kaplan-Meier survival analysis with Log-rank test and Cox proportional hazards regression analysis were performed.

The 5-year overall survival (OS) rate in the HN group was the highest (32.2%). Multivariate analyses indicated that the HN group (HR 0.520, 95% CI 0.309–0.878, P = 0.014), female sex (HR 0.685, 95% CI 0.498–0.944, P = 0.021), serum CRP level (HR 1.057, 95% CI 1.034–1.080, P < 0.001), chemotherapy (HR 0.324, 95% CI 0.228–0.460, P < 0.001), and chemotherapy/radiotherapy (HR 0.266, 95% CI 0.171–0.414, P < 0.001) were independent prognostic factors for overall survival.

In advanced NSCLC, patients with baseline high serum CEA but low CYFRA 21-1 level have a significant longer overall survival regardless of clinical stage.

To explore the ability of MALAT1 to influence non-small cell lung cancer (NSCLC) A549 cells in vitro and tumor xenograft growth in vivo by modulating autophagy.

LncRNA MALAT-1 in normal HBE cells and human NSCLC cells was measured. A549 cells were treated with si-MALAT-1, negative control and si-MALAT-1 + rapamycin. The mRNA levels of MALAT-1, P62 and LC3 was determined by the qRT-PCR and the protein levels of autophagy-related proteins by the western blotting. The CCK8 assay was performed for cell proliferation, the scratch test for cell migration, the Transwell assay for cell invasion, and the flow cytometry for cell cycle and apoptosis. Tumor xenograft in nude mice is performed to test tumorigenesis of the transfected A549 cells.

The expression level of MALAT-1 in A549, SPC-A-1 and NCI-H460 cells was increased compared to HBE cells. And A549 with a high expression level of MALAT-1 were selected for cell transfection. si-MALAT-1 decreased cell proliferation, migration, invasion, and LC3-II/LC3-I ratio, reduced cell cycle progression, and increased cell apoptosis and P62 protein expression. No significant difference was found between A549 cells and A549 cells transfected with si-MALAT-1 + RAPA, A549 cells transfected with NC and A549 cells transfected with si-MALAT-1 + RAPA. Nude mice injected with A549 cells transfected with si-MALAT-1 had smallest tumor on size and weight among other nude mice.

Downregulation of MALAT1 may promote apoptosis and suppress proliferation, migration and invasion of human NSCLC A549 cells by inhibiting autophagy, thereby suppressing the development of NSCLC.

Circulating microRNAs (miRNAs) play an essential role in the development and progression of acute myeloid leukemia (AML). However, the clinical value of serum miR-217 in AML remained poorly known.

This study aimed to explore the clinical significance of serum miR-217 in AML.

Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed to detect miR-217 levels in the blood samples obtained from 89 AML patients and 60 healthy controls.

The results showed that miR-217 expression was significantly decreased in AML patients compared to controls. Likewise, serum miR-217 levels were greatly downregulated in the AML patients with poor risk cytogenetic. ROC analysis demonstrated that serum miR-217 could effectively differentiate AML patients from normal controls. Also, miR-217 expression was markedly increased in patients achieving complete remission after their treatment. In addition, low miR-217 expression was associated with aggressive clinical features. Moreover, Kaplan-Meier analysis showed that AML patients with low miR-217 expression tended to have shorter overall survival and disease free survival. In the multivariate analysis stratified for prognostic parameters, miR-217 was proved to be an independent prognostic indicator.

Collectively, miR-217 was identified as an independent marker for the diagnosis and prognosis of AML.

Accumulating studies have reported the abnormal expression of microRNA-136 (miR-136) in numerous types of human cancer, and its involvement in cancer initiation and progression. However, there are no investigations of miR-136 in osteosarcoma (OS).

To explore the expression pattern, clinical significance and potential roles of miR-136 in OS.

miR-136 expression in clinical OS tissues and human OS cell lines were detected by qPCR, and its associations with clinicopathological characteristics of OS patients were statistically analyzed. Then, the effects of miR-136 on OS cell proliferation, migration and invasion were assessed in vitro. Its underling mechanisms were also investigated.

miR-136 expression in OS tissues and cells were dramatically decreased compared with corresponding non-cancerous tissues and cells, respectively. Low miR-136 expression was significantly associated with aggressive clinical features, including the advanced clinical stage, the presence of lung and distant metastasis (all P < 0.05). Additionally, enforced expression of miR-136 obviously inhibited the proliferation, migration and invasion of OS cells in vitro. Mechanistically, metadherin (MTDH) was predicted and verified as a target gene of miR-136. Further functional experiments indicated that the loss of MTDH abrogated the tumor suppressive roles of miR-136 in OS cells.

Our findings provide the first evidence that the aberrant expression of miR-136 may be implicated into carcinogenesis and cancer progression of OS. Functionally, miR-136 may inhibit the proliferation, migration and invasion of OS cells via negatively regulating its target gene MTDH. Thus, miR-136-MTDH axis may be a potential therapeutic targets for the treatment of OS.

Colorectal cancer is the third most common cancer in economically developed countries. Molecular studies and, in particular, gene expression have contributed to advances in the diagnosis and treatment of many cancers. Genes can be molecular and therapeutic markers, but because of the large molecular diversity in colorectal cancer the knowledge is not yet fully established. Probably one of the most crucial processes during early cancer development is inflammation. The inflammatory response in the tumor is an important indicator of molecular etiology and later of cancer progression.

The aim of this work is to identify potential biomarkers for early stage of colorectal adenocarcinoma in patients’ bowel tissues using transcriptomic analysis.

Expression of the inflammatory response genes of colorectal cancer at all clinical stages (I–IV) and control of the bowel were evaluated by oligonucleotide microarrays.

Based on statistical analysis many differentially expressed genes were selected. LCK (LCK Proto-Oncogene, Src Family Tyrosine Kinase), GNLY (granulysin), SLC6A6 (Solute-Carrier Family 6 Member 6) and LAMP2 (Lysosomal Associated Membrane Protein 2) were specific for the early stage of the disease. These genes had the properties of the good biomarkers.

The expression of LCK, GNLY, SLC6A6 and LAMP2 genes could be valuable potential diagnostic biomarkers of the early stage of colorectal adenocarcinoma.

Azacitidine (AZA) is a nucleoside analog used for treatment of myelodysplasia and the prediction of AZA responsiveness is important for the therapy management.

Using microarrays and reverse-transcription quantitative-PCR, we analyzed microRNA (miRNA) expression in bone marrow CD34+ cells of 27 patients with higher-risk myelodysplastic syndromes or acute myeloid leukemia with myelodysplasia-related changes before and during AZA treatment.

At baseline, we found that future overall response rate was significantly higher in patients with upregulated miR-17-3p and downregulated miR-100-5p and miR-133b. Importantly, the high level of miR-100-5p at baseline was associated with shorter overall survival (HR = 4.066, P = 0.008). After AZA treatment, we observed deregulation of 30 miRNAs in responders (including downregulation of miR-10b-5p, miR-15a-5p/b-5p, miR-24-3p, and miR-148b-3p), while their levels remained unchanged in non-responders.

Our study demonstrates that responders and non-responders have distinct miRNA patterns and that the level of specific miRNAs before therapy may predict the efficacy of AZA treatment.

miR-126 functions as a tumor suppressor in gastric cancer (GC), however, the clinical significance of serum miR-126 in GC remains unclear.

To investigate the associations of serum miR-126 level with the clinicopathological characteristics and prognosis of GC patients.

Quantitative real-time polymerase chain reaction was performed to examine the expression levels of miR-126 in 338 GC patients’ tissues and sera, and 50 healthy controls’ sera. The associations of serum miR-126 with clinicopathological characteristics and clinical outcome were evaluated.

Compared with the matched adjacent non-tumor tissues and normal sera, miR-126 expression was significantly down-regulated in both tumor tissues and sera of GC patients. Importantly, there was a positive correlation between tissue and serum levels of miR-126 in GC patients. A reduced serum miR-126 level statistically correlated with aggressive clinicopathological characteristics, such as larger tumor size, deeper local invasion, more lymph node metastasis, advanced TNM stage, and poorer prognosis. Notably, multivariate analysis identified reduced serum miR-126 level as an independent predictor for the unfavorable prognosis of GC.

These results indicate for the first time that serum miR-126 may serve as a novel prognostic biomarker in GC.

Circular RNAs (circRNA)are involved in the progression of cancers, and previous study showed that hsa_circ_0001649 expression is down-regulated in hepatocellular carcinoma (HCC).

To explore whether hsa_circ_0001649 is a prognostic biomarker for HCC and to investigate the biological functions of hsa_circ_0001649 in HCC.

Hsa_circ_0001649 expression was measured in 77 pairs of HCC and adjacent no-tumor tissues by quantitative Real-Time polymerase chain reaction. Kaplan-Meier curve and Cox regression were used to analyze its prognostic significance for HCC patients. In addition, the hsa_circ_0001649 was over-expressed using a circRNA-forming plasmid in HCC cells, and the biological function of hsa_circ_0001649 was investigated in vitro.

We verified that hsa_circ_0001649 was down-regulated in HCC tissues compared with adjacent non-tumor tissues. In addition, low hsa_circ_0001649 expression was associated with the poor overall survival of HCC patients, and Cox multivariate analysis showed that hsa_circ_0001649 is a novel independent prognostic factor for HCC patients. Furthermore, the in vitro experiments demonstrated that over-expressed hsa_circ_0001649 inhibits the proliferation, migration, and invasion and promotes the apoptosis of HCC cells.

Hsa_circ_0001649 could act as a novel prognostic biomarker for HCC patients. In addition, hsa_circ_ 0001649 might be a potential therapeutic target for HCC.

The potential prognostic value of survivin is variably reported depending on the gastric cancer.

Evaluation of the prognostic and predictive significance of serum survivin and its relation with survival and treatment response rates in patients with locally advanced gastric cancer (LAGC).

Serum samples were prospectively collected from 50 patients with newly diagnosed LAGC. Serum samples of 32 healthy subjects were also collected as control groups for survivin levels. Serum survivin levels were evaluated at baseline and after three cycles of neoadjuvant chemotherapy in LAGC patients.

: Median survivin level was 147 IU/L (range = 4.4–4936) at baseline and was 27 IU/L (range = 4.2–4737) after neoadjuvant chemotherapy. The difference between survivin levels of the control group (26 IU/L, range = 3.8–1430) and pre-treatment patient group was statistically significant ( p < 0.001). Clinical response to mDCF regimen was classified as progressive (progressive disease) and non-progressive groups (partial response + stable disease). Baseline survivin levels were similar between patients in progressive and non-progressive groups ( p = 0.55). Survivin levels were significantly reduced after chemotherapy in non-progressive group ( p < 0.001). In contrast, serum survivin levels increased in a stepwise fashion from baseline to post-chemotherapy in patients with progressive disease ( p = 0.06). Patients were divided into low and high survivin groups according to baseline median survivin levels. Median DFS was 12.4 and 14.6 months for low and high groups, respectively ( p = 0.18). Moreover, median OS was 14.4 and 24.9 months for low and high group, respectively ( p = 0.14).

It can be suggested that serum survivin can be used as a predictor of response to chemotherapy- but not survival- in LAGC patients receiving neoadjuvant mDCF chemotherapy. However, large multicenter prospective studies are required to confirm these results.

MicroRNAs (miRNAs) were identified to be involved in various biological functions by regulating the degradation or suppressing the translation of their downstream target genes. Recent studies have identified miR-29a acts as tumor suppressor in hepatocellular carcinoma (HCC) progression. However, the underlying functions for miR-29a in HCC still to be investigated.

The expression of miR-29a expression in HCC tissues and corresponding adjacent normal tissues was detected using qRT-PCR analyses. Cell proliferation ability was assessed using CCK8 assay, cell colony forming and flow cytometry analysis. Bioinformatics, the dual luciferase reporter assay, qRT-PCR and western blot analysis were used to demonstrate that SIRT1 was a target of miR-29a.

Here, we demonstrated that miR-29a was significantly downregulated in HCC tissues compared with corresponding adjacent normal tissues. Lower miR-29a expression associated with tumor size and vascular invasion of HCC. Furthermore, Lower miR-29a predicted a poor disease free survival (DFS) and overall survival (OS) time for HCC patients. Function assays showed that overexpression of miR-29a effectively suppressed cell proliferation, cell colony forming ability, and cell cycle progression. MiR-29a overexpression also inhibited the cell cycle related protein expression of CyclinD1 and CDK4, but increasing the P21 expression. Furthermore, Bioinformatics and the dual luciferase reporter assay analysis results demonstrated that miR-29a specifically targeted the 3’-UTR of SIRT1 mRNA and regulated its protein expression. Increased SIRT1 expression rescued the inhibited effects induced by miR-29a overexpression in HCC cells.

Thus, these results indicated that miR-29a may serve as a potential target of HCC treatment.

Adjuvant chemotherapy plays important role in the comprehensive treatment of patients with stage III colorectal cancer. However, there is few molecular markers for predicting the therapeutic effect.

To identify factors that could predict adjuvant chemotherapy benefits in patients with stage III colorectal cancer.

The medical records of 294 patients were reviewed and analyzed using the Kaplan–Meier method and Cox analysis.

Lower CA125 ( ⩽ 35 u/ml, P = 0.0015) serum levels, stage IIIa ( P = 0.0027), 1-3 positive lymph nodes ( P = 0.0256), negative vascular invasion ( P = 0.0215), lower CA199 ( ⩽ 27 u/ml, P = 0.0038) serum levels, and wild-type BRAF status ( P = 0.0125) were significantly associated with a higher 2-year DFS rate in patients with stage III colorectal cancer. However, in multivariate COX analysis, the association remained significant only for CA125 levels (vs. ⩽ 35 u/ml group, HR 3.341; 95% CI, 1.198–9.316; P = 0.0212), vascular invasion (vs. negative vascular invasion, HR, 2.349; 95% CI, 1.227–4.499; P = 0.01), and BRAF (V600E) (vs. wild Braf, HR, 7.794; 95% CI, 1.867–32.531; P = 0.0049).

Lower CA125 serum levels, negative vascular invasion, and wild-type BRAF status were significantly associated with improved 2-year DFS rates among patient with stage III disease who received adjuvant chemotherapy.

Recent study revealed that abnormal long noncoding RNAs (lncRNAs) expression are association with chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC).

The present study was aimed to investigate the effects of lncRNA AB209630 expression for gemcitabine resistance in PDAC cells.

In the study, increased expression of lncRNA AB209630 could suppress cell proliferation and cell colony formation ability in gemcitabine resistance cells of PDAC. Furthermore, western blot results demonstrated that upregulation of lncRNA AB209630 suppressed the PI3K/AKT signaling pathway in gemcitabine resistance cells. Besides, we found that lncRNA AB209630 expression was dramatically downregulated in PDAC tissues compared to adjacent normal tissues. Lower PDAC expression predicted a poor prognosis in PDAC patients.

Thus, these results indicated that lncRNA AB209630 may be a potential target of PDAC.