Cancer Biomarkers - Volume 39, issue 3

Authors: Aluksanasuwan, Siripat | Somsuan, Keerakarn | Ngoenkam, Jatuporn | Chutipongtanate, Somchai | Pongcharoen, Sutatip

Article Type: Research Article

Abstract: BACKGROUND: Lung adenocarcinoma (LUAD) is a major histological subtype of lung cancer with a high mortality rate worldwide. Heat shock protein family D member 1 (HSPD1, also known as HSP60) is reported to be increased in tumor tissues of lung cancer patients compared with healthy control tissues. OBJECTIVE: We aimed to investigate the roles of HSPD1 in prognosis, carcinogenesis, and immune infiltration in LUAD using an integrative bioinformatic analysis. METHODS: HSPD1 expression in LUAD was investigated in several transcriptome-based and protein databases. Survival analysis was performed using the KM plotter and OSluca databases, …while prognostic significance was independently confirmed through univariate and multivariate analyses. Integrative gene interaction network and enrichment analyses of HSPD1-correlated genes were performed to investigate the roles of HSPD1 in LUAD carcinogenesis. TIMER and TISIDB were used to analyze correlation between HSPD1 expression and immune cell infiltration. RESULTS: The mRNA and protein expressions of HSPD1 were higher in LUAD compared with normal tissues. High HSPD1 expression was associated with male gender and LUAD with advanced stages. High HSPD1 expression was an independent prognostic factor associated with poor survival in LUAD patients. HSPD1-correlated genes with prognostic impact were mainly involved in aberrant ribosome biogenesis, while LUAD patients with high HSPD1 expression had low tumor infiltrations of activated and immature B cells and CD4+ T cells. CONCLUSIONS: HSPD1 may play a role in the regulation of ribosome biogenesis and B cell-mediated immunity in LUAD. It could serve as a predictive biomarker for prognosis and immunotherapy response in LUAD. Show more

Keywords: Lung adenocarcinoma, HSPD1, ribosome biogenesis, immune infiltration, biomarker, prognosis

DOI: 10.3233/CBM-220442

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 155-170, 2024

Authors: Miao, Shidi | Jia, Haobo | Huang, Wenjuan | Cheng, Ke | Zhou, Wenjin | Wang, Ruitao

Article Type: Research Article

Abstract: OBJECTIVES: This study explores a deep learning (DL) approach to predicting bone metastases in breast cancer (BC) patients using clinical information, such as the fat index, and features like Computed Tomography (CT) images. METHODS: CT imaging data and clinical information were collected from 431 BC patients who underwent radical surgical resection at Harbin Medical University Cancer Hospital. The area of muscle and adipose tissue was obtained from CT images at the level of the eleventh thoracic vertebra. The corresponding histograms of oriented gradients (HOG) and local binary pattern (LBP) features were extracted from the CT images, …and the network features were derived from the LBP and HOG features as well as the CT images through deep learning (DL). The combination of network features with clinical information was utilized to predict bone metastases in BC patients using the Gradient Boosting Decision Tree (GBDT) algorithm. Regularized Cox regression models were employed to identify independent prognostic factors for bone metastasis. RESULTS: The combination of clinical information and network features extracted from LBP features, HOG features, and CT images using a convolutional neural network (CNN) yielded the best performance, achieving an AUC of 0.922 (95% confidence interval [CI]: 0.843–0.964, P < 0.01). Regularized Cox regression results indicated that the subcutaneous fat index was an independent prognostic factor for bone metastasis in breast cancer (BC). CONCLUSION: Subcutaneous fat index could predict bone metastasis in BC patients. Deep learning multimodal algorithm demonstrates superior performance in assessing bone metastases in BC patients. Show more

Keywords: Breast cancer, bone metastases, deep learning, subcutaneous fat, multimodalityKey points:•Subcutaneous fat index is an independent prognostic factor for bone metastasis in BC patients;•A multimodal model using computed tomography (CT) images, local binary pattern (LBP) features, and histograms of oriented gradient (HOG) features can effectively predict bone metastases;•The mask-guided attention mechanism effectively makes the model focus on the fat area.

DOI: 10.3233/CBM-230219

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 171-185, 2024

Authors: Li, Qi | Zhao, Min | Hu, Dan-Dan | Qin, Jun-Jiao | He, Wei

Article Type: Research Article

Abstract: BACKGROUND: Circular RNAs (circRNAs) are critical regulators of lung adenocarcinoma (LA) progression. Although a molecular marker targeting hsa_circ_0000018 has been developed and used for diagnosing colon cancer, the role of this circRNA in LA progression has not been explored till now. OBJECTIVES: This study aimed to elucidate the role and regulatory mechanisms of hsa_circ_0000018 in LA progression. METHODS: LA tissues and corresponding adjacent non-tumor tissues were collected from 36 patients to confirm the levels of circRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We also cultured two …LA cell lines (A549, PC-9), and the human normal lung epithelial cell line BEAS-2B. Cell function experiments were conducted to assess malignancy in LA cells, including proliferation, migration, and invasion, following forced hsa_circ_0000018 expression. The correlation between hsa_circ_0000018, let-7f-5p, and family with sequence similarity 96 member A (FAM96A) was confirmed by using starBase (miRNA-circRNA interaction database), luciferase assay, and western blotting. RESULTS: Expression of hsa_circ_0000018 and FAM96A was reduced, whereas that of let-7f-5p was upregulated in LA. Cell function assays revealed that upregulation of hsa_circ_0000018 had a suppressive effect on the proliferation, migration, and invasion of LA cells. Additionally, hsa_circ_0000018 sponge binds let-7f-5p, resulting in upregulation of FAM96A expression. CONCLUSION: Our data reveal hsa_circ_0000018 as a tumor suppressor in LA that targets the let-7f-5p/FAM96A axis. Our findings enrich the known regulatory network of circRNAs in LA. Show more

Keywords: hsa_circ_0000018, lung adenocarcinoma, let-7f-5p, FAM96A, circRNAs

DOI: 10.3233/CBM-230111

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 187-195, 2024

Authors: Peng, Shuang | Zhang, Hao | Song, Guoxin | Zhu, Jingfeng | Zhang, Shiyu | Liu, Cheng | Gao, Feng | Yang, Hang | Zhu, Wei

Article Type: Research Article

Abstract: BACKGROUND: Post-transcriptional regulation of mRNA induced by microRNA is known crucial in tumor occurrence, progression, and metastasis. This study aims at identifying significant miRNA-mRNA axes for stomach adenocarcinomas (STAD). METHOD: RNA expression profiles were collected from The Cancer Genome Atlas (TCGA) and GEO database for screening differently expressed RNAs and miRNAs (DE-miRNAs/DE-mRNAs). Functional enrichment analysis was conducted with Hiplot and DAVID-mirPath. Connectivity MAP was applied in compounds prediction. MiRNA-mRNA axes were forecasted by TarBase and MiRTarBase. Real-time reverse transcription polymerase chain reaction (RT-qPCR) of stomach specimen verified these miRNA-mRNA pairs. Diagnosis efficacy of miRNA-mRNA interactions was …measured by Receiver operation characteristic curve and Decision Curve Analysis. Clinical and survival analysis were also carried out. CIBERSORT and ESTIMATE was employed for immune microenvironment measurement. RESULT: Totally 228 DE-mRNAs (105 upregulated and 123 downregulated) and 38 DE-miRNAs (22 upregulated and 16 downregulated) were considered significant. TarBase and MiRTarBase identified 18 miRNA-mRNA pairs, 12 of which were verified in RT-qPCR. The network of miR-301a-3p/ELL2 and miR-1-3p/ANXA2 were established and verified in external validation. The model containing all 4 signatures showed better diagnosis ability. Via interacting with M0 macrophage and resting mast cell, these miRNA-mRNA axes may influence tumor microenvironment. CONCLUSION: This study established a miRNA-mRNA network via bioinformatic analysis and experiment validation for STAD. Show more

Keywords: miRNA, miRNA-mRNA networks, stomach adenocarcinoma, TCGA, PCR

DOI: 10.3233/CBM-230125

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 197-210, 2024

Authors: Attia, Amany Selim | Hussein, Samia | Sameh, Hend | Khalil, Amr | Waley, Ahmad Barakat | Matar, Ihab | Sameh, Reham

Article Type: Research Article

Abstract: BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignancy. Histopathological examination is widely accepted as the gold standard test for the diagnosis of PTC. However, the histopathological examination sometimes can’t differentiate PTC from other thyroid diseases. Differentiating PTC from other thyroid diseases is essential for a therapeutic approach and prognosis. OBJECTIVES: The current study was performed to investigate the utility of TROP-2, SPL-2, and CXCL12 mRNA and protein expression in discriminating PTC from other thyroid diseases that mimic PTC. METHODS: The current study was performed on 75 cases of surgically resected …thyroid glands. The cases were distributed in two groups: the PTC group and the non-PTC group. The PTC group consisted of 35 cases (25 patients of the classic PTC variant and 10 patients of the PTC follicular variant). The non-PTC group consisted of 40 cases (10 cases were multinodular goiter, 5 cases were Graves’ disease, 5 cases were Hashimoto thyroiditis, 15 patients were follicular adenoma (FA) and 5 cases were follicular carcinoma). TROP-2 , SPL-2 , and CXCL12 mRNA expression were estimated by qRT-PCR, and protein expression was estimated by immunohistochemistry. RESULTS: There were upregulated TROP-2, SPL-2, and CXCL12 mRNA and protein expressions in PTC compared to non-PTC (P < 0.001, for each). There was a statistically significant upregulation in the mRNA expression of the three genes among PTC cases with larger tumor sizes (P < 0.001, for each), those with tumor stages III and IV (P = 0.008, 0.002 and < 0.001 respectively), and those with LN metastasis (P < 0.001, for each). Moreover, there was a statistically significant upregulation in CXCL-12 gene expression among PTC cases with extra-thyroid extension (P < 0.001). CONCLUSION: mRNA expression of TROP-2, SPL-2, and CXCL12 among PTC cases increased in larger tumor size, tumor stages III and IV, and LN metastasis. Moreover, there was an increase in CXCL-12 gene expression among PTC cases with extra-thyroid extension. Thus, TROP-2, SPL-2, and CXCL12 expressions could be possible diagnostic and prognostic markers in PTC. Show more

Keywords: TROP-2, SPL-2, CXCL12, papillary thyroid carcinoma

DOI: 10.3233/CBM-230230

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 211-221, 2024

Authors: Zhang, Xuan | Wu, Yang-Yang | Qin, Yuan-Yuan | Lin, Fa-Quan

Article Type: Research Article

Abstract: OBJECTIVE: This article aims to investigate the clinical value of hemoglobin/red cell distribution width ratio (Hb/RDW), C-reactive protein/albumin ratio (CAR) and plateletcrit (PCT) combined with carcinoembryonic antigen (CEA) in colorectal cancer (CRC) auxiliary diagnosis. METHODS: We retrospectively analyzed in 718 subjects (212 with CRC, 209 with benign colorectal lesions (BCL), 111 with other cancers, and 186 healthy controls). RESULTS: The CAR, PCT, and CEA in the CRC group were higher than those in the BCL, other cancers, and the healthy control group. However, Hb/RDW in the CRC group was lower than the other …three groups. Moreover, there were significant differences in Hb/RDW and CEA among different T-N-M stages (all P < 0.05). Multivariate logistic regression showed that low level of Hb/RDW and high level of CAR, CEA, PCT were risk factors for CRC, and are correlated with CRC stage. Additionally, the area under the receiver operating characteristic curve (AUC) of Hb/RDW+ CEA (AUC: 0.735), CAR+ CEA (AUC: 0.748), PCT+ CEA (AUC: 0.807) was larger than that of Hb/RDW (AUC: 0.503), CAR (AUC: 0.614), or PCT (AUC: 0.713) alone (all P < 0.001) in distinguishing CRC from BCL. CONCLUSIONS: Hb/RDW, CAR, PCT, and CEA are independent risk factors for CRC. Hb/RDW, CAR, and PCT combined with CEA have significant value for auxiliary differential diagnosis of CRC and BCL. Show more

Keywords: Hemoglobin/red cell distribution width ratio, C-reactive protein/albumin ratio, plateletcrit, carcinoembryonic antigen, colorectal cancer

DOI: 10.3233/CBM-230157

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 223-230, 2024

Authors: Qu, Xinjian | Xu, Chang | Yang, Wenbo | Li, Qianqian | Tu, Simei | Gao, Chenghai

Article Type: Research Article

Abstract: BACKGROUND: Epithelial-mesenchymal transition (EMT) is an important biological process by which malignant tumor cells to acquire migration and invasion abilities. This study explored the role of KLF5 in the EMT process of in cervical cancer cell lines. OBJECTIVE: Krüpple-like factor 5 (KLF5) is a basic transcriptional factor that plays a key role in cell-cycle arrest and inhibition of apoptosis. However, the molecular mechanism by which KLF5 mediates the biological functions of cervical cancer cell lines has not been elucidated. Here, we focus on the potential function of ELF5 in regulating the EMT process in in vitro …model of cervical cancer cell lines. METHOD: Western-blot and real-time quantitative PCR were used to detect the expression of EMT-related genes in HeLa cells. MTT assays, cell scratch and Transwell assays were used to assess HeLa cells proliferation and invasion capability. Using the bioinformatics tool JASPAR, we identified a high-scoring KLF5-like binding sequence in the SNAI1 gene promoter. Luciferase reporter assays was used to detect transcriptional activity for different SNAI1 promoter truncates. RESULT: After overexpressing the KLF5 gene in HeLa cells, KLF5 not only significantly inhibited the invasion and migration of HeLa cells, but also increased the expression of E-cadherin and decreased the expression of N-cadherin and MMP9. In addition, the mRNA expression of upstream regulators of E-cadherin, such as SNAI1, SLUG, ZEB1/2 and TWIST1 was also decreased. Furthermore, KLF5 inhibiting the expression of the SNAI1 gene via binding its promoter region, and the EMT of Hela cells was promoted after overexpression of the SNAI1 gene. CONCLUSION: These results indicate that KLF5 can downregulate the EMT process of HeLa cells by decreasing the expression of the SNAI1 gene, thereby inhibiting the migration and invasion of HeLa cervical cancer cells. Show more

Keywords: KLF5, EMT, SNAI1, cervical cancer cells

DOI: 10.3233/CBM-230175

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 231-243, 2024

Authors: Corlett, Ryan | Button, Charles | Scheel, Sydney | Agrawal, Swati | Rai, Vikrant | Nandipati, Kalyana C.

Article Type: Research Article

Abstract: Esophageal adenocarcinoma (EAC) occurs following a series of histological changes through epithelial-mesenchymal transition (EMT). A variable expression of normal and aberrant genes in the tissue can contribute to the development of EAC through the activation or inhibition of critical molecular signaling pathways. Gene expression is regulated by various regulatory factors, including transcription factors and microRNAs (miRs). The exact profile of miRs associated with the pathogenesis of EAC is largely unknown, though some candidate miRNAs have been reported in the literature. To identify the unique miR profile associated with EAC, we compared normal esophageal tissue to EAC tissue using bulk RNA …sequencing. RNA sequence data was verified using qPCR of 18 selected genes. Fourteen were confirmed as being upregulated, which include CDH11, PCOLCE, SULF1, GJA4, LUM, CDH6, GNA12, F2RL2, CTSZ, TYROBP, and KDELR3 as well as the downregulation of UGT1A1 . We then conducted Ingenuity Pathway Analysis (IPA) to analyze for novel miR-gene relationships through Causal Network Analysis and Upstream Regulator Analysis. We identified 46 miRs that were aberrantly expressed in EAC compared to control tissues. In EAC tissues, seven miRs were associated with activated networks, while 39 miRs were associated with inhibited networks. The miR-gene relationships identified provide novel insights into potentially oncogenic molecular pathways and genes associated with carcinogenesis in esophageal tissue. Our results revealed a distinct miR profile associated with dysregulated genes. The miRs and genes identified in this study may be used in the future as biomarkers and serve as potential therapeutic targets in EAC. Show more

Keywords: Esophageal adenocarcinoma, RNA sequencing, microRNA, therapeutic target, biomarkers, hub gene

DOI: 10.3233/CBM-230170

Citation: Cancer Biomarkers, vol. 39, no. 3, pp. 245-264, 2024