Cancer Biomarkers - Volume 31, issue 3

Authors: Tan, Benxu | Chen, Yonghong | Xia, Lei | Yu, Xian | Peng, Yuan | Zhang, Xiaoyue | Yang, Zhenzhou

Article Type: Research Article

Abstract: BACKGROUND: Prostate transmembrane protein androgen-induced 1 (PMEPA1), a critical checkpoint of multiple signaling pathways, has been demonstrated to play a crucial role in various types of cancers. However, little is known about its function in non-small cell lung cancer (NSCLC). OBJECTIVE: Our objective is to explore the function of PMEPA1 and its potential mechanisms in NSCLC progression. METHODS: PMEPA1 expression and prognostic significance in adenocarcinoma of lung cancer (LUAD) and squamous cell carcinoma of lung cancer (LUSC) were determined using Gene Expression Profiling Interactive Analysis (GEPIA). Next, a series of cell assays were …performed to examine whether overexpression or depletion of PMEPA1 affected the malignant behaviors of NSCLC H1299 cells, such as proliferation and migration. Luciferase reporter gene assays and SP600125 (a JNK inhibitor) were employed to ascertain the regulatory relationship between PMEPA1 and JNK. RESULTS: PMEPA1 is overexpressed in LUAD and LUSC tissues and portends a worse prognosis for cancer patients. Gain and loss of function experiments demonstrated that PMEPA1 executes oncogenetic function in H1299 cells. Mechanism studies elucidated that PMEPA1 stimulated the transcriptional activity of the JNK pathway. CONCLUSION: PMEPA1 increased the H1299 cell viability, proliferation, and migration which works, at least partially, by triggering the JNK activity. Hence, our findings support that the PMEPA1/JNK axis might be a promising therapeutic target for this challenging disease. Show more

Keywords: PMEPA1, JNK, non-small cell lung cancer, proliferation, migration

DOI: 10.3233/CBM-200966

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 203-210, 2021

Authors: Zhang, Feng | Hu, Ke-Shu | Lu, Shen-Xin | Li, Miao | Chen, Rong-Xin | Ren, Zheng-Gang | Shi, Ying-Hong | Yin, Xin

Article Type: Research Article

Abstract: BACKGROUND: Inflammation-based prognostic scores have been increasingly used for prognosis prediction in malignant tumors. However, no existing study has comprehensively evaluated these scores in combined hepatocellular-cholangiocarcinoma (cHCC-CCA). OBJECTIVE: This study aimed to identify a robust inflammation-based prognostic predictor for cHCC-CCA. METHODS: We retrospectively analyzed 220 patients pathologically confirmed as Allen type C cHCC-CCA. The univariate and multivariate analyses were used to explore the associations between clinical variables and prognosis of cHCC-CCA. The propensity score-matching (PSM) was performed to reduce the effects of potential cofounders and selection bias. Finally, the predictive values of different …inflammation-based indices were compared by using time-dependent receiver operating characteristic (ROC) curves. RESULTS: The systemic immune-inflammation index (SII) and aspartate aminotransferase to platelet ratio index (APRI) were identified as independent prognostic predictors in multivariate analysis. After PSM, the survival differences were still significant between SII-high group and SII-low group (P = 0.016 for RFS and P = 0.001 for OS). Further ROC analysis showed that the SII harbored the largest 1-, 3- and 5-year area under the curves (AUC) values as compared with other scores. CONCLUSIONS: The SII may serve as a preferable predictor of both recurrence-free survival (RFS) and overall survival (OS) in patients with cHCC-CCA. Show more

Keywords: Combined hepatocellular-cholangiocarcinoma, systemic immune-inflammation index, propensity score-matching, overall survival, recurrence-free survival

DOI: 10.3233/CBM-200643

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 211-225, 2021

Authors: Li, Yanlei | Sun, Ran | Zhao, Xiulan | Sun, Baocun

Article Type: Research Article

Abstract: BACKGROUND: Runt-related transcription factor 2 (RUNX2) is an important gene that has been implicated in the progression of human cancer. Aberrant expression of RUNX2 predicts gastric cancer (GC) metastasis. However, the molecular mechanism of RUNX2 remains unknown. OBJECTIVE: We hypothesize that RUNX2 promotes GC metastasis by regulating the extracellular matrix component collagen type I alpha 1 (COL1A1). METHODS: The GEPIA database and immunohistochemical staining of 60 GC tissues were used to analyse the correlations between RUNX2 or COL1A1 expression and clinicopathological features, and the Kaplan-Meier method was used to evaluate survival. …RT-PCR, western blotting and immunofluorescence were used to detect RUNX2 and COL1A1 expression in GC cells. Migration and invasion assays were performed to assess the influence of RUNX2 and COL1A1 on metastasis. RESULTS: RUNX2 and COL1A1 were highly expressed at both the gene and protein levels in GC, and patients who were positive for RUNX2 and COL1A1 had shorter survival. RUNX2 and COL1A1 expression linearly correlated with each other (r = 0.15, p < 0.01) and with clinical stage and lymph node metastasis (p < 0.05). Overexpressing RUNX2 in vitro enhanced COL1A1 expression and promoted GC cell invasion and migration, whereas COL1A1 knockdown inhibited the increase in cell metastatic capacity promoted by RUNX2. In vivo , GC cells overexpressing RUNX2 promoted lung metastasis, and the downregulation of COL1A1 reduced the metastasis promoted by RUNX2 . CONCLUSIONS: RUNX2 may promote GC metastasis by regulating COL1A1. RUNX2/COL1A1 can be employed as a novel target for therapy in GC. Show more

Keywords: RUNX2, COL1A1, metastasis, gastric cancer

DOI: 10.3233/CBM-200472

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 227-238, 2021

Authors: Wang, Yang | He, Bo | Dong, Yan | He, Gong-Jing | Qi, Xiao-Wei | Li, Yan | Yang, Yi-Fei | Rao, Yu | Cen, Zhong-Shun | Han, Fei | Ding, Jun | Li, Jian-Jun

Article Type: Research Article

Abstract: BACKGROUND: The prognosis of lung cancer patients is poor without useful prognostic and diagnostic biomarker. To search for novel prognostic and diagnostic markers, we previously found homeobox-A13 (HOXA13) as a promising candidate in lung cancer. OBJECTIVE: To determine the precisely clinical feature, prognostic and diagnostic value, possible role and mechanism of HOXA13. METHODS: Gene-expression was explored by real-time quantitative-PCR, western-blot and tissue-microarray. The associations were analyzed by Chi-square test, Kaplan-Meier and Cox-regression. The roles and mechanisms were evaluated by MTS, EdU, transwell, xenograft tumor and luciferase-reporter assays. RESULTS: HOXA13 expression …is increased in tumors, and correlated with age of patients. HOXA13 expression is associated with unfavorable overall survival and relapse-free survival of patients in four cohorts. Interestingly, HOXA13 has different prognostic significance in adenocarcinoma (ADC) and squamous-cell carcinoma (SCC), and is a sex- and smoke-related prognostic factor only in ADC. Importantly, HOXA13 can serve as a diagnostic biomarker for lung cancer, especially for SCC. HOXA13 can promote cancer-cell proliferation, migration and invasion in vitro , and facilitate tumorigenicity and tumor metastasis in vivo . HOXA13 acts the oncogenic roles on tumor growth and metastasis by regulating P53 and Wnt/β -catenin signaling activities in lung cancer. CONCLUSIONS: HOXA13 is a new prognostic and diagnostic biomarker associated with P53 and Wnt/β -catenin signaling pathways. Show more

Keywords: Overall survival, diagnostic marker, homeobox-A13, oncogene, P53 signaling, Wnt/β-catenin signaling, non-small cell lung cancer

DOI: 10.3233/CBM-200540

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 239-254, 2021

Authors: Xiong, Hao | Zhang, Xinwen | Chen, Xiaomin | Liu, Yang | Duan, Jialin | Huang, Chunlan

Article Type: Research Article

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is one of the most malignant hematopoietic system diseases. Interferon stimulated exonuclease gene 20 (ISG20) is a protein induced by interferons or double-stranded RNA, which is associated with poor prognosis in several malignant tumors. However its expression in AML is unknown. OBJECTIVE: To explore the expression of ISG20 in AML and its prognostic significance. METHODS: The expression of ISG20 in AML patients was analyzed by GEPIA database, detected by qRT-PCR and their prognosis was followed-up. Chi-square test was used to identify the association between ISG20 expression and clinical …characteristics of the patients. Kaplan-Meier analysis was performed to draw survival curves and Cox regression analysis to confirm the independent prognostic factors of AML patients. RESULTS: Kaplan-Meier analysis revealed that whether to receive treatment, karyotype, and ISG20 expression were related to overall survival time of AML patients (P < 0.05). Cox regression analysis showed that whether to receive treatment (HR = 0.248, 95% CI = 0.076–0.808, P = 0.021) and high expression of ISG20 (HR = 4.266, 95% CI = 1.118–16.285, P = 0.034) were independent unfavorable prognostic factors for AML patients. CONCLUSION: The high expression of ISG20 acts as a poor prognosis indicator in AML patients. Show more

Keywords: Acute myeloid leukemia, ISG20, survival times, prognosis, interferon

DOI: 10.3233/CBM-210061

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 255-261, 2021

Authors: Huang, Meifang | Li, Tianqian | Wang, Qing | Li, Chongxin | Zhou, Huahua | Deng, Shengyi | Lv, Zengbo | He, Yongmei | Hou, Bo | Zhu, Guangying

Article Type: Research Article

Abstract: BACKGROUND: Radiotherapy is one of main useful therapies in non-small cell lung cancer (NSCLC). Nevertheless, the underlying mechanism between NSCLC cell radiosensitivity and effective treatment remains unclear. OBJECTIVE: The aim is to explore the relationship between circular (circ) RNA and NSCLC cell radiosensitivity. METHODS: CircRNA plasmacytoma variant translocation 1 (PVT1) and microRNA (miR)-1208 expression in NSCLC cells were assessed using quantitative reverse transcriptase PCR (qRT-PCR). NSCLC cells were transfected with si-PVT1 or miR-1208 inhibitor and then exposed to irradiation. Cellular biology behaviors were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Terminal deoxynucleotidyl transferase dUTP Nick-End …Labeling (TUNEL), colony formation, invasion and western blot. Additionally, binding between circPVT1 and miR-1208 was testified by dual-luciferase reporter and RIP assay. RESULTS: CircPVT1 was upregulated in NSCLC cells after irradiation treatment. Silencing circPVT1 induced inhibition of NSCLC cell growth and invasion, accompanied by cell apoptosis and γ -H2AX expression. Moreover, NSCLC cell proliferation and invasion was further inhibited by irradiation treatment in circPVT1-silenced cells, indicating a strong radiosensitivity of NSCLC cells. CircPVT1 functions as a competing endogenous RNA of miR-1208. Silencing miR-1208 reversed NSCLC cell sensitivity response to irradiation and activated PI3K/AKT/mTOR pathway in circPVT1-silenced cells. CONCLUSIONS: Silencing circPVT1 enhanced radiosensitivity of NSCLC cells by sponging miR-1208. Show more

Keywords: NSCLC, circPVT1, miR-1208, radiosensitivity, PI3K/AKT/mTOR signaling

DOI: 10.3233/CBM-203252

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 263-279, 2021

Authors: Janpipatkul, Keatdamrong | Trachu, Narumol | Watcharenwong, Piyakarn | Panvongsa, Wittaya | Worakitchanon, Wittawin | Metheetrairut, Chanatip | Oranratnachai, Songporn | Reungwetwattana, Thanyanan | Chairoungdua, Arthit

Article Type: Research Article

Abstract: BACKGROUND: Osimertinib is an epidermal growth factor receptor-tyrosine kinase inhibitor that specifically targets the T790M mutation in cancer.Unfortunately, most non-small cell lung cancer (NSCLC) patients develop osimertinib resistance. Currently, the molecular biomarkers for monitoring osimertinib resistance are not available. OBJECTIVE: This study aimed to examine the profile of exosomal miRNA in the plasma of osimertinib-resistant NSCLC patients. METHODS: Plasma exosomal miRNA profiles of 8 NSCLC patients were analyzed by next-generation sequencing at osimertinib-sensitive and osimertinib-resistance stage.The expression of dysregulated exosomal miRNAs was validated and confirmed in another cohort of 19 NSCLC patients by …qPCR. The relationship between exosomal miRNA upregulation and clinical prognosis, survival analysis was evaluated by Kaplan-Meier curves. RESULTS: In osimertinib-resistant NSCLC patients, 10 exosomal miRNAs were significantly dysregulated compared to baseline. Upregulation of all 10 candidate exosomal miRNAs tended to correlate with increased latency to treatment failure and improved overall survival. Among them, 4 exosomal miRNAs, miR-323-3p, miR-1468-3p, miR-5189-5p and miR-6513-5p were essentially upregulated and show the potential to be markers for the discrimination of osimertinib-resistance from osimertinib-sensitive NSCLC patients with high accuracy (p < 0.0001). CONCLUSIONS: Our results highlight the potential role of these exosomal miRNAs as molecular biomarkers for the detection of osimertinib resistance. Show more

Keywords: Osimertinib resistance, NSCLC, exosome, miRNA, biomarker

DOI: 10.3233/CBM-203075

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 281-294, 2021

Authors: Li, Meng | Zhang, Wenmin | Yang, Xiaodan | An, Guo | Zhao, Wei

Article Type: Research Article

Abstract: BACKGROUND: The voltage-gated calcium channel subunit alpha 2 delta 1 (α 2δ 1) is a functional tumor initial cells (TICs) marker for some solid cancer cells. This study aimed to investigate whether α 2δ 1 can be used as a potential TIC marker for breast cancer cells. METHODS: α 2δ 1 + and α 2δ 1 - cells were identified and sorted from the breast cancer cell lines MDA-MB-231, MDA-MB-435s and ZR-75-1 by …Immunofluorescence (IF) and Fluorescent-activated cell sorting (FACS) analyses. Spheroid formation in vitro and tumorigenesis in NOD/SCID mice were assessed to determine the self-renewal and serial transplantation abilities of these cells. Using a lentivirus infection system for α 2δ 1 in breast cancer cell lines, we determined the mRNA levels of stemnessassociated genes by quality real-time PCR (qRT-PCR). Boyden chamber and wounding assays were further performed to detect the migration of α 2δ 1 overexpression cells. Bioinformatics explored the relationship of molecular classification of breast cancer and drug resistance. RESULTS: α 2δ 1 presents on the cytomembrane of breast cancer cells, with a positive rate of 1.5–3%. The α 2δ 1 + cells in breast cancer cell lines have a stronger self-renewal ability and tumor initiating properties in vitro and in vivo . Overexpressing α 2δ 1 successfully enhanced the sphere-forming efficiency, and upregulated the expression of stemness-associated genes, and increased cell migration. However, seldom significant was available between estrogen receptor +/- (ER+/-), progesterone receptor (PR+/-), and Her2+/-. CONCLUSIONS: Breast cancer cells positive for the α 2δ 1 charactered tumor initiation, and α 2δ 1 is a potential TIC marker for breast cancer that further promotes the migration. Show more

Keywords: α2δ1, TIC, breast cancer, biomarker

DOI: 10.3233/CBM-203165

Citation: Cancer Biomarkers, vol. 31, no. 3, pp. 295-305, 2021