Cancer Biomarkers - Volume 34, issue 3

Authors: Okabe, Seiichi | Tanaka, Yuko | Gotoh, Akihiko

Article Type: Research Article

Abstract: BACKGROUND: Although Abelson (ABL) tyrosine kinase inhibitors (TKIs) have demonstrated potency against chronic myeloid leukemia (CML), resistance to ABL TKIs can develop in CML patients after discontinuation of therapy. OBJECTIVE: Glucose metabolism may be altered in CML cells because glucose is a key metabolite used by tumor cells. We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. METHODS: We investigated whether D-mannose treatment induced metabolic changes in CML cells and reduced CML growth in the presence of ABL TKIs. …RESULTS: Treatment with D-mannose for 72 h inhibited the growth of K562 cells. Combined treatment using ABL TKIs and D-mannose induced a significantly higher level of cytotoxicity in Philadelphia chromosome (Ph)-positive leukemia cells than in control cells. In the mouse model, severe toxicity was observed as evidenced by body weight loss in the ponatinib and D-mannose combination treatment groups. CONCLUSION: Our results indicate that metabolic reprogramming may be a useful strategy against Ph-positive leukemia cells. However, caution should be exercised during clinical applications. Show more

Keywords: Chronic myeloid leukemia, D-mannose, glycolysis, ABL tyrosine kinase inhibitor

DOI: 10.3233/CBM-210141

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 337-346, 2022

Authors: Gilbert, Laura | Ratnam, Sam | Jang, Dan | Alaghehbandan, Reza | Schell, Miranda | Needle, Rob | Ecobichon-Morris, Anne | Wadhawan, Arnav | Costescu, Dustin | Elit, Laurie | Wang, Peter | Zahariadis, George | Chernesky, Max

Article Type: Research Article

Abstract: OBJECTIVES & METHODS: CINtec PLUS and cobas HPV tests were compared for triaging patients referred to colposcopy with a history of LSIL cytology in a 2-year prospective study. Cervical specimens were tested once at enrollment, and test positivity rates determined. Test performance was ascertained with cervical intraepithelial neoplasia grade 2 or worse (CIN2+ ) and CIN3 or worse (CIN3+ ) serving as clinical endpoints. RESULTS: In all ages, (19–76 years, n = 598), 44.3% tested CINtec PLUS positive vs. 55.4% HPV positive (p < …0.001). To detect CIN2+ (n = 99), CINtec PLUS was 81.8% sensitive vs. 93.9% for HPV testing (p = 0.009); genotype 16/18-specific sensitivity was 46.5%. Specificity was 52.9% vs. 36.6%, respectively (p < 0.001). In all ages, to detect CIN3+ (n = 44), sensitivity was 93.2% for both tests; genotype 16/18-specific sensitivity was 52.3%. Specificity was 48.4% for CINtec PLUS vs. 31.1% for HPV testing (p < 0.001). In patients < 30 years, CINtec was 91.7% sensitive vs 95.8% for HPV testing (p = 0.549). CONCLUSIONS: CINtec PLUS or cobas HPV test could serve as a predictor of CIN3+ with high sensitivity in patients referred to colposcopy with a history of LSIL regardless of age while significantly reducing the number of LSIL referral patients requiring further investigations and follow-up in colposcopy clinics. Show more

Keywords: p16/Ki-67 dual-stain cytology, CINtec PLUS cytology, cobas HPV test, human papillomavirus (HPV) triage, low-grade squamous intraepithelial lesion (LSIL) triage, cervical intraepithelial neoplasia grade 2 or worse (CIN2+), cervical intraepithelial neoplasia grade 3 or worse (CIN3+)

DOI: 10.3233/CBM-210366

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 347-358, 2022

Authors: Li, Yixue | Liu, Hengrui

Article Type: Research Article

Abstract: BACKGROUND: Head and neck squamous cell carcinoma (HNSC) is one of the most common cancer types in the world. The study in molecular markers for HNSC prognosis is of great significance. We hypothesized that Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1), a gene that encodes a cytokine, is a critical biomarker for HNSC. METHODS: We acquired clinical data, mRNA expression data, protein staining data, and single-cell expression data of HNSC from open databases and evaluated the clinical prognostic value of AIMP1, and explored the potential roles of AIMP1 in HNSC biology and tumor immune …microenvironment. RESULTS: AIMP1 was overexpressed in HNSC compared to normal tissues. Higher AIMP1 expression was associated with a worse survival rate. A survival nomogram was constructed for HNSC patients. One thousand two hundred and eighty-one genes were identified as positively associated with AIMP1 and enriched in proliferation-related terminologies, while 303 genes were identified as negatively associated with AIMP1 and enriched in terminologies related to skin development and immune cell regulation. AIMP1 was positively correlated with stemness, cell cycle, and DNA repair, and negatively correlated with angiogenesis, quiescence, metastasis, hypoxia, inflammation, EMT, DNA damage, and invasion in single cells. AIMP1 was expressed higher in malignant cells than immune cells and there was no difference in AIMP1 expression among immune cell types. AIMP1 high group had a lower immune score, stroma score, and microenvironment score. CONCLUSION: AIMP1 is a potential diagnostic and prognostic biomarker for HNSC patients and can potentially affect the proliferation and tumor immune microenvironment of HNSC cells. This study provided a novel molecular marker for the improvement of clinical HNSC treatment. Show more

Keywords: AIMP1, HNSC, gene expression, survival, immune cells

DOI: 10.3233/CBM-210340

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 359-374, 2022

Authors: Tan, Wei-Qiang | Yuan, Li | Wu, Xiao-Yan | He, Cheng-Guang | Zhu, Shai-Cheng | Ye, Ming

Article Type: Research Article

Abstract: Accumulating evidence validates that aerobic glycolysis is involved in chemotherapy resistance in human malignant tumors. In the present study, we explored the role of exosome-delivered circular RNA DLGAP4 (circDLGAP4), a novel identified circRNAs, in the chemoresistance of neuroblastoma (NB) cells. Our study demonstrated that doxorubicin-resistant cells expressed higher HK2, accompanied with enhanced glycolysis. In addition, circDLGAP4 was validated to act as a sponge for the HK2-targeting miR-143. As a molecular cargo, exosomes were found to deliver circDLGAP4 from doxorubicin-resistant cells to the sensitive cells. Functionally, exosomal circDLGAP4 enhanced glycolysis and drug resistance via regulating miR-143 and HK2 in NB cells. …Consistently, upregulation of HK2 induced by circDLGAP4 or miR-143 inhibitors produced the similar malignant transformation in NB cells. However, knockdown of circDLGA P4 could reversed the drug resistance in the recipient cells. In conclusion, these findings demonstrate that exosome-delivered circDLGAP4 promotes the glycolysis, proliferation, and invasion of sensitive NB cells by regulating miR-143 and HK2, providing a novel link between drug resistance and circDLGAP4/miR-143/HK2 axis in drug-resistant NB. Show more

Keywords: Neuroblastoma, exosomes, CircDLGAP4, glycolysis, drug resistance

DOI: 10.3233/CBM-210272

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 375-384, 2022

Authors: Gottlin, Elizabeth B. | Campa, Michael J. | Gandhi, Rikesh | Bushey, Ryan T. | Herndon 2nd, James E. | Patz Jr., Edward F.

Article Type: Research Article

Abstract: BACKGROUND: Biomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis. OBJECTIVES: The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence. METHODS: …Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level. RESULTS: In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray’s test, P = 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P = 0.4670). CONCLUSIONS: The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence. Show more

Keywords: NSCLC, prognosis, biomarkers, autoantibodies

DOI: 10.3233/CBM-210355

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 385-392, 2022

Authors: Zou, Jiayue | Gu, Yanlin | Zhu, Qi | Li, Xiaohua | Qin, Lei

Article Type: Research Article

Abstract: PURPOSE: Functions associated with glycolysis could serve as targets or biomarkers for therapy cancer. Our purpose was to establish a prognostic model that could evaluate the importance of Glycolysis-related lncRNAs in breast cancer. METHODS: Gene expressions were evaluated for breast cancer through The Cancer Genome Atlas (TCGA) database, and we calculated Pearson correlations to discover potential related lncRNAs. Differentially expressed genes were identified via criteria of FDR < 0.05 and | FC| > 2. Total samples were separated into training and validating sets randomly. Univariate Cox …regression identified 14 prognostic lncRNAs in training set. A prognostic model was constructed to evaluate the accuracy in predicting prognosis. The univariate and multivariate Cox analysis were performed to verify whether lncRNA signature could be an independent prognostic factor The signature was validated in validating set. Immune infiltration levels were assessed. RESULTS: Eighty-nine differentially expressed lncRNAs were identified from 420 Glycolysis-related lncRNAs. 14 lncRNAs were correlated with prognosis in training set and were selected to establish the prognostic model. Low risk group had better prognosis in both training (p = 9.025 e -10) and validating (p = 4.272 e -3) sets. The univariate and multivariate Cox analysis revealed that risk score of glycolysis-related lncRNAs (P < 0.001) was an independent prognostic factor in both training and validating sets. The neutrophils (p = 4.214 e -13, r = - 0.223), CD4+ T cells (p = 1.833 e -20, r = - 0.283), CD8+ T cells (p = 7.641 e -12, r = - 0.211), B cells (p = 2.502 e -10, r = - 0.195) and dendritic cells (p = 5.14 e -18, r = - 0.265) were negatively correlated with risk score of prognostic model. The Macrophage (p = 0.016, r = 0.0755) was positively correlated with the risk score. CONCLUSION: Our study indicated that glycolysis-related lncRNAs had a significant role to facilitate the individualized survival prediction in breast cancer patients, which would be a potential therapeutic target. Show more

Keywords: Glycolysis, breast cancer, LncRNA

DOI: 10.3233/CBM-210446

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 393-401, 2022

Authors: Ali, Mona Mostafa | Mohamed, Rania Hassan | Sayed, Ahmed A. | Ahmed, Sonia | Yassin, Dina A. | El-Sayed, Wael M.

Article Type: Research Article

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is characterized by heterogeneity in phenotypic, genotypic, and clinical traits. miRNAs play an important role in pathogenesis and diagnosis of adult AML. Such information is not available about miRNA expression role in pediatric AML. OBJECTIVE: We aimed to investigate the expression of miR-370 and miR-375 as new diagnostic biomarkers to discriminate pediatric AML patients and to predict their roles in the disease molecular basis. METHODS: The expression of both miR-370 and miR-375 in peripheral blood (PB) of pediatric AML patients was assessed by QPCR; their impact for diagnosis …was evaluated by ROC curve and their roles in pediatric AML development were predicted by bioinformatics analysis. RESULTS: The expression of miR-370 and miR-375 levels was significantly decreased in pediatric AML patients, suggesting them as tumor suppressor miRNAs as supported by bioinformatics analysis. miR-370 showed better potential and sensitivity toscreen pediatric AML patients and more significant correlation with AML risk than miR-375. This is the first study to report the positive correlation between both miR-370 and miR-375. CONCLUSION: miR-370 level in peripheral blood can serve as a potential non-invasive diagnostic biomarker and was significantly correlated with AML risk. We strongly recommend PB miRNAs as diagnostic biomarkers for pediatric AML. Show more

Keywords: Pediatric AML, diagnosis, microRNA, miR-375, miR-370, biomarkers

DOI: 10.3233/CBM-210360

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 403-411, 2022

Authors: Gibriel, Abdullah Ahmed | Ismail, Manal Fouad | Sleem, Hameis | Zayed, Naglaa | Yosry, Ayman | El-Nahaas, Saeed M. | Shehata, Nagwa Ibrahim

Article Type: Research Article

Abstract: BACKGROUND: Chronic HCV infection progresses to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The latter represents the third most common cause for cancer mortality. Currently, there is no reliable non-invasive biomarker for diagnosis of HCV mediated disorders. OBJECTIVE: Profiling expression signature for circulatory miRNAs in the plasma of 167 Egyptian patients (40 healthy, 48 HCV fibrotic, 39 HCV cirrhotic and 40 HCV-HCC cases). METHODS: QRTPCR was used to quantify expression signature for circulatory miRNAs. RESULTS: MiR-676 and miR-650 were powerful in discriminating cirrhotic and late fibrosis from HCC. MiR-650 could distinguish mild …(f0-f1) and advanced (f2-f3) fibrosis from HCC cases. MiR-650 and miR-147b could distinguish early fibrosis from healthy controls meanwhile miR-676 and miR-147b could effectively distinguish between mild chronic and (f1-f3) cases from healthy individuals. All studied miRNAs, except miR-512, can differentiate between (f0-f3) cases and healthy controls. Multivariate logistic regression revealed three potential miRNA panels for effective differentiation of HCC, cirrhotic and chronic liver cases. MiR-676-3p and miR-512-5p were significantly correlated in (f1-f3) fibrosis meanwhile miR-676 and miR-512 could differentiate between cirrhosis and (f0-f3) cases. Both miR-650 and miR-512-5p were positively correlated in the cirrhotic group and in (f0-f4) group. Putative targets for investigated miRNAs were also determined. CONCLUSIONS: Investigated miRNAs could assist in staging and diagnosis of HCV associated disorders. Show more

Keywords: Biomarkers, HCV, miRNA, HCC, fibrosis

DOI: 10.3233/CBM-210456

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 413-430, 2022

Authors: Han, Haibo | Pan, Bo | Liang, Fan | Wu, Lina | Liu, Xijuan | Yang, Yue | Chen, Jinfeng

Article Type: Research Article

Abstract: BACKGROUND: MicroRNAs can regulate tumor metastasis either as oncomiRs or suppressor miRNAs. Here, we investigated the role of microRNA 224 (miR-224) in lymphatic metastasis of non-small-cell lung cancer (NSCLC). METHODS: The expression of miR-224 was demonstrated by a validation cohort of 156 lung cancer patients (77 cases with lymphatic metastasis) by quantitative polymerase chain reaction (qPCR). In vitro and in vivo experiments were performed to study the malignant phenotype after upregulation and inhibition of miR-224 expression. Furthermore, the direct target genes of miR-224 were determined by a luciferase reporter assay. RESULTS: …First, miR-224 was identified as a highly expressed miRNA in tumor tissues with lymphatic metastasis, with an area under the curve (AUC) of 0.57 as determined by qPCR analysis of a validation cohort of 156 lung cancer patients. Then, in vitro and in vivo experiments indicated that forced expression of miR-224 in H1299 cells promoted not only cell viability, plate colony formation, migration and invasion in vitro but also tumor growth and lung metastasis in vivo . Consistently, inhibition of miR-224 suppressed malignant characteristics both in vitro and in vivo . Moreover, molecular mechanistic research suggested that miR-224 enhanced NSCLC by directly targeting the tumor suppressor angiopoietin-like protein (ANGPTL). CONCLUSIONS: Overall, the collective findings demonstrate that miR-224 is a potential biomarker for the prediction of lymphatic metastasis of NSCLC. Show more

Keywords: microRNA, miR-224, on-small-cell lung cancer, lymphatic metastasis, ANGPTL

DOI: 10.3233/CBM-210376

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 431-441, 2022

Authors: Zhang, Li | Zhao, Yao | Guan, Hao | Zhang, Di

Article Type: Research Article

Abstract: BACKGROUND: Long non-coding RNAs have drawn increasing research interest in cancer biology. This study aims to investigate the function roles and the underlying mechanism of HnRNPU-AS1 in Hepatocellular carcinoma (HCC). METHODS: qRT-PCR was performed to detect the expression levels of HnRNPU-AS1, miR-556-3p, miR-580-3p in HCC tissues and cell lines. Western blot was used to determine protein levels of LC3-II, LC3-I, Beclin-1, P62, and SOCS6. Functional assays including CCK8 assay, colony formation assay, wound healing assay, Transwell assay were performed to evaluate the role of HnRNPU-AS1 in regulating the malignant phenotype of HCC cells. Dual luciferase reporter …assay and RNA pull-down experiment were used to examined the RNA-RNA interaction. RESULTS: HnRNPU-AS1 expression was decreased in HCC tissues and cell lines, which was associated with poor prognosis in HCC patients. Overexpression of HnRNPU-AS1 could inhibit the proliferation, migration, invasion but promote autophagy in HCC cells. Two miRNAs (miR-556-3p and miR-580-3p) were identified as potential targets of HnRNPU-AS1 in lncBASE database, which were significantly upregulated in HCC tissues and cell lines. Cell experiments demonstrated the effects of HnRNPU-AS1 overexpression could be attenuated by miR-556-3p or miR-580-3p overexpression. We further revealed that SOX6 was the downstream target of HnRNPU-AS1/miR-556-3p or miR-580-3p axis. Xenograft mouse model validated the tumor-suppressor role of HnRNPU-AS1 overexpression in vivo . CONCLUSIONS: This study demonstrated the tumor suppressor function of HnRNPU-AS1 in HCC and identified the downstream molecules underlying its tumor suppressor function. Our results suggest that HnRNPU-AS1 suppresses HCC by targeting miR-556-3p and miR-580-3p/SOXS6 axis. Show more

Keywords: Hepatocellular carcinoma (HCC), HnRNPU-AS1, miR-556-3p, miR-580-3p, SOXS6, autophagy

DOI: 10.3233/CBM-210261

Citation: Cancer Biomarkers, vol. 34, no. 3, pp. 443-457, 2022