Cancer Biomarkers - Volume 31, issue 2

Authors: Zhang, Meng-Lin | Huang, Wen-Juan | Yue, Chen-Xi | Li, Ming-Ming | Li, Na | Wang, Rui-Tao | Xie, Rui

Article Type: Research Article

Abstract: BACKGROUND: Platelets play a key role in tumor progression and metastasis. C-type lectin-like receptor 2 (CLEC-2) is the receptor expressed on platelets and the marker of platelet activation. OBJECTIVE: This study aims to determine whether soluble CLEC-2 levels differ between patients with benign colorectal polyps and those with colorectal cancer (CRC). METHODS: We measured plasma soluble CLEC-2 by enzyme-linked immunosorbent assay in 150 patients with colorectal polyps, 150 CRC patients without metastasis, 150 CRC liver metastasis, and 150 control subjects. RESULTS: The CRC patients had higher soluble CLEC-2 levels than …patients with colorectal polyps (p < 0.001). Moreover, CRC patients with liver metastases displayed higher CLEC-2 levels than those in CRC patients without metastases (p < 0.001). In the CRC patients, CLEC-2 levels were correlated with lymph node metastasis and advanced stage. In the patients with polyps, there was a significant difference in CLEC-2 levels among patients with hyperplastic polyp, sessile serrated adenoma, and traditional serrated adenoma (p < 0.001). The ROC curve analysis revealed CLEC-2 had an optimal sensitivity of 77.3% and specificity of 94.6% for the screening of CRC, and sensitivity of 71.0% and specificity of 76.7% for the differential diagnosis of colorectal polyps and CRC. CONCLUSIONS: CRC patients have higher CLEC-2 levels than patients with colorectal polyps and healthy controls. Moreover, there is a significant difference in CLEC-2 levels among polyp subtypes. Further research is warranted. Show more

Keywords: Colorectal cancer, polyps, c-type lectin-like receptor 2

DOI: 10.3233/CBM-200734

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 99-105, 2021

Authors: Ye, Mujie | He, Jiajun | Zhang, Jingjing | Liu, Baihui | Liu, Xiangqi | Xie, Lulu | Wei, Meng | Dong, Rui | Li, Kai | Ma, Duan | Dong, Kuiran

Article Type: Research Article

Abstract: BACKGROUND: Hepatoblastoma (HB) is an embryonic solid tumor and the most common primary malignant liver tumor in children. HB usually occurs in infants and children. Although treatment diversity is increasing, some patients still have very poor prognosis. Many studies have investigated USP7 inhibitors for tumors. Using database information, we found that USP7 is highly expressed in HB. METHODS: Lentivirus-mediated USP7 knockdown and overexpression was performed in HB cell lines HepG2 and Huh6. CCK8 and transwell assays were used to determine cell viability and metastasis. Flow cytometry was used to study cell cycle and apoptosis. Levels of …proteins were detected using western blots. RESULTS: Downregulation of USP7 resulted in significant decrease in cell proliferation, clonal formation, and cell migration and invasion. With overexpression of USP7, cellular malignant behavior increased. Cell cycle assays showed that USP7 knockdown inhibited G1 to S phase transition in the cell cycle. Upregulation of USP7 promoted the transition. Animal experiments showed USP7 facilitated tumor growth in vivo . Western blots indicated that USP7 may affect HB tumorigenesis through the PI3K/AKT signaling pathway. Furthermore, USP7 inhibitor P5091 inhibited HB development and PI3K/AKT pathway. CONCLUSION: USP7 upregulation contributed to HB genesis and development through the PI3K/AKT signaling pathway. USP7 could be a potential target for future HB treatment. Show more

Keywords: Hepatoblastoma, signaling pathway, inhibitor, apoptosis, proliferation, metastasis

DOI: 10.3233/CBM-200052

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 107-117, 2021

Authors: Fukui, Tomoya | Sakai, Kazuko | Sasaki, Jiichiro | Kakegawa, Mikiko Ishihara | Igawa, Satoshi | Mitsufuji, Hisashi | Takeda, Masayuki | Takahama, Takayuki | Nakagawa, Kazuhiko | Nishio, Kazuto | Naoki, Katsuhiko

Article Type: Research Article

Abstract: BACKGROUND: The advancement of cancer genomics has allowed for multiplex gene assays using next-generation sequencing (NGS) to be practically implemented, however, a clinical practice system remains to be established. OBJECTIVE: We evaluated the feasibility of clinical sequencing using NGS-based multiplex gene assays between cooperating medical institutions in patients with advanced cancers. METHODS: In this observational study, DNA and RNA samples prepared from existing tumor tissues were subjected to comprehensive genomic profiling using targeted sequencing. RESULTS: From January 2017 to March 2019, 36 samples from 33 patients were assessed. Of all …patients, 27 (82%) had lung cancer, with the median age of 50 years (range 38–83). Multiplex gene panel tests were successfully carried out on 35/36 (97%) samples. Potentially actionable gene alterations were identified in 10/30 (33%) samples (3 HER2 , 2 KRAS , 2 ALK , 1 PIK3CA , 1 RET , and 1 CDKN2A ). In the 6 samples examined for resistant mechanisms, ALK I1171N mutation and MET copy number gain were detected in 2 patients with ALK rearrangement-positive lung cancer. CONCLUSIONS: Clinical sequencing using NGS-based multiplex gene assays between collaborating domestic medical institutions was feasible, with a success rate of > 97%. Overall, clinical sequencing benefits therapeutic decision-making in patients with advanced cancer. Show more

Keywords: Clinical sequencing, multiplex gene assay, next-generation sequencing, driver mutation, resistant mechanism

DOI: 10.3233/CBM-200781

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 119-126, 2021

Authors: Fan, Xingchen | Cao, Minmin | Liu, Cheng | Zhang, Cheng | Li, Chunyu | Cheng, Wenfang | Zhang, Shiyu | Zhang, Huo | Zhu, Wei

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs (miRNAs), with noticeable stability and unique expression pattern in plasma of patients with various diseases, are powerful non-invasive biomarkers for cancer detection including endometrial cancer (EC). OBJECTIVE: The objective of this study was to identify promising miRNA biomarkers in plasma to assist the clinical screening of EC. METHODS: A total of 93 EC and 79 normal control (NC) plasma samples were analyzed using Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) in this four-stage experiment. The receiver operating characteristic curve (ROC) analysis was conducted to evaluate the diagnostic value. Additionally, the expression features …of the identified miRNAs were further explored in tissues and plasma exosomes samples. RESULTS: The expression of miR-142-3p, miR-146a-5p, and miR-151a-5p was significantly overexpressed in the plasma of EC patients compared with NCs. Areas under the ROC curve of the 3-miRNA signature were 0.729, 0.751, and 0.789 for the training, testing, and external validation phases, respectively. The diagnostic performance of the identified signature proved to be stable in the three public datasets and superior to the other miRNA biomarkers in EC diagnosis. Moreover, the expression of miR-151a-5p was significantly elevated in EC plasma exosomes. CONCLUSIONS: A signature consisting of 3 plasma miRNAs was identified and showed potential for the non-invasive diagnosis of EC. Show more

Keywords: Plasma microRNA, endometrial carcinoma, diagnostic biomarker, qRT-PCR

DOI: 10.3233/CBM-200972

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 127-138, 2021

Authors: El-Benhawy, Sanaa A. | Ebeid, Samia A. | Abd El Moneim, Nadia A. | Arab, Amal R.R. | Ramadan, Rabie

Article Type: Research Article

Abstract: BACKGROUND: Altered cadherin expression plays a vital role in tumorigenesis, angiogenesis and tumor progression. However, the function of protocadherin 17 (PCDH17) in breast cancer remains unclear. OBJECTIVE: Our target is to explore PCDH17 gene expression in breast carcinoma tissues and its relation to serum angiopoietin-2 (Ang-2), carbonic anhydrase IX (CAIX) and % of circulating CD34 + cells in breast cancer patients (BCPs). METHODS: This study included Fifty female BCPs and 50 healthy females as control group. Cancerous and neighboring normal breast tissues were collected from BCPs as well as …blood samples at diagnosis. PCDH17 gene expression was evaluated by RT-PCR. Serum Ang-2, CAIX levels were measured by ELISA and % CD34 + cells were assessed by flow cytometry. RESULTS: PCDH17 was downregulated in cancerous breast tissues and its repression was significantly correlated with advanced stage and larger tumor size. Low PCDH17 was significantly correlated with serum Ang-2, % CD34 + cells and serum CAIX levels. Serum CAIX, Ang-2 and % CD34 + cells levels were highly elevated in BCPs and significantly correlated with clinical stage. CONCLUSIONS: PCDH17 downregulation correlated significantly with increased angiogenic and hypoxia biomarkers. These results explore the role of PCDH17 as a tumor suppressor gene inhibiting tumor growth and proliferation. Show more

Keywords: Breast cancer, PCDH17, Ang-2, CD34, serum CAIX

DOI: 10.3233/CBM-201593

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 139-148, 2021

Authors: Arslan, Özge | Soylu, Neşe Karadağ | Akillilar, Pelin Telkoparan | Tazebay, Uygar H.

Article Type: Research Article

Abstract: BACKGROUND: Coiled-coil domain containing protein-124 (Ccdc124) is a putative mRNA-binding factor associated with cell division, and ribosome biology. Previous reports mentioned an up-regulation of CCDC124 gene in cancer, and listed its mRNA in a molecular prognostic signature in breast cancer. OBJECTIVES: Establishing RNA-binding characteristics of Ccdc124 for a better molecular functional characterization, and carrying-out retrospective studies in order to evaluate its aberrant expression in human cancer samples from various tissue origins. METHODS: Bioinformatics calculations followed by RIP and RNA-seq experiments were performed to investigate mRNA targets of Ccdc124. Quantitative studies on arrays …of cDNAs from different cancers and IHC assays on tissue arrays were used to assess CCDC124 expression levels in cancers. RESULTS: Ccdc124 was characterized as an RNA-binding protein (RBP) interacting with various mRNAs. CCDC124 mRNA levels were high in tumors, with a particular up-regulation in cancers from esophagus, adrenal gland, endometrium, liver, ovary, thyroid, and urinary bladder. IHC assays indicated strong Ccdc124 positivity in endometrial (95.4%), urinary bladder (68.4%), and ovarian cancers (86.8%). CONCLUSION: Ccdc124 is a cytokinesis related RBP interacting with various mRNAs. CCDC124 mRNA over-expression and an accompanied increase in Ccdc124 protein accumulation was reported in cancers, indicating this RBP as a novel cancer cell marker. Show more

Keywords: Cancer biomarkers, coiled-coil domain-containing protein-124, RNA-binding proteins, gynecological cancers, ovarian cancer, urinary bladder cancer

DOI: 10.3233/CBM-200802

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 149-164, 2021

Authors: Zhao, Yuxin | Ma, Shuwen | Cui, Zhigang | Li, Sixuan | Chen, Yao | Yin, Yu | Yin, Zhihua

Article Type: Research Article

Abstract: BACKGROUND: More and more studies have shown that long non-coding RNA (LncRNA) as a competing endogenous RNA (ceRNA) plays an important role in lung cancer. Therefore, we analyzed the RNA expression profiles of 82 lung cancer patients which were all from Gene Expression Omnibus (GEO). METHODS: Firstly, we used BLASTN (evalue = 1e - 10 ) to annotate the gene sets, performed in-group correction and batched normalization of the three data sets with R. Secondly, we used the limma and sva packages to compare tumor tissues with normal tissues. …Then through WGCNA, we obtained the 4 gene modules most related to the trait. RESULTS: We intersected the genes of above 4 modules with the differential expression genes: 28 LncRNAs (up: 5, down: 23) and 265 mRNAs (up:11, down: 254). Based on these genes, we picked up 6 LncRNAs (CCDC39, FAM182A, SRGAP3-AS2, ADAMTS9-AS2, AC020907.2, SFTA1P), then set and visualized the LncRNA-miRNA-mRNA ceRNA network with 12 miRNAs related to 12 mRNAs. Finally, we performed downstream analysis of 265 mRNAs by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network. CONCLUSION: After analyzing, we think this study provides a new direction for basic and clinical research related to LAD, and is expected to provide new targets for early diagnosis, prognostic evaluation and clinical treatment of lung cancer. Show more

Keywords: Lung adenocarcinoma, GEO, LncRNA, ceRNA, WGCNA

DOI: 10.3233/CBM-203078

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 165-176, 2021

Authors: Qi, Weixiang | Zhao, Shengguang | Chen, Jiayi

Article Type: Research Article

Abstract: BACKGROUND: To investigate the prognostic role of lung immune prognostic index (LIPI) in extensive-stage small-cell lung cancer (ES-SCLC) patients treated with platinum plus etoposide chemotherapy. METHODS: Data were obtained from two randomized controlled trials (NCT00119613 and NCT00363415). Overall survival (OS) and progression-free survival (PFS) was assessed according to LIPI score through Kaplan-Meier analysis. Univariate and multivariate Cox-regression analysis were performed to investigate predictors for OS and PFS. RESULTS: A total of 911 patients with ES-SCLC treated with platinum plus etoposide chemotherapy (CT) were included for analysis. The median age at diagnosis was 62 …years, and 760 (83.4%) had performance status of 1 or less. 1-year OS for ES-SCLC with poor, intermediate, and good LIPI was 20%, 30% and 31%, respectively, and 1-year PFS was 7%, 15% and 21%, respectively. Cox-regression analysis showed that the PFS and OS of ES-SCLC with a poor LIPI score was significantly worse than those with good LIPI scores (HR 1.81, 95% CI: 1.38–2.36; p < 0.001 and HR 1.35, 95% CI: 1.07–1.72, p = 0.012), while no significant difference was observed between intermediate and poor LIPI groups in terms of OS (HR 1.01, 95% CI: 0.82–1.23, p = 0.82), but not for PFS (HR 1.27, 95% CI: 1.00–1.61, p = 0.048). In addition, LIPI score was significantly associated with disease control rate and objective response rate (both p < 0.0001). CONCLUSION: Prognosis of patients with pretreatment LIPI score of 2 is poorer than those with LIPI score of 0–1 among ES-SCLC who received first-line platinum plus etoposide chemotherapy; Further studies are still recommended to confirm our findings in prospective studies. Show more

Keywords: Small-cell lung cancer, biomarker, LIPI score, prognostic index

DOI: 10.3233/CBM-201502

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 177-185, 2021

Authors: Xu, Ping | Mo, Xiao | Xia, Ruixue | Jiang, Long | Zhang, Chengfei | Xu, Haojun | Sun, Qi | Zhou, Guoren | Zhang, Yijie | Wang, Yongsheng | Xia, Hongping

Article Type: Research Article

Abstract: BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell …and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug. Show more

Keywords: KCNN4, lung adenocarcinoma, AKT, ERK, proliferation

DOI: 10.3233/CBM-201045

Citation: Cancer Biomarkers, vol. 31, no. 2, pp. 187-201, 2021