Cancer Biomarkers - Volume 37, issue 4

Authors: Pecqueux, Mathieu | Wende, Beate | Sommer, Ulrich | Baenke, Franziska | Oehme, Florian | Hempel, Sebastian | Aust, Daniela | Distler, Marius | Weitz, Jürgen | Kahlert, Christoph

Article Type: Research Article

Abstract: BACKGROUND: Pancreatic cancer is the 4th leading cause of cancer-related death with poor survival even after curative resection. RAB27A and RAB27B are key players in the exosome pathway where they play important roles in exosome secretion. Evidence suggests that RAB27A and RAB27B expression not only leads to tumor proliferation and invasion, but also plays an important role in antigen transfer necessary for anticancer immunity. OBJECTIVE: In this study, we analyze the expression of RAB27A and RAB27B in patients after pancreatic cancer surgery with or without adjuvant chemotherapy and its influence on overall survival. METHODS: …We analyzed a total of 167 patients with pancreatic cancer for their RAB27A and RAB27B expression. We dichotomized the patients along the median and compared survival in patients with high and low RAB27A and RAB27B expression with or without adjuvant chemotherapy treatment. RESULTS: We found a significant improvement in overall survival in patients with a negative resection margin (p = 0.037) and in patients who received adjuvant chemotherapy (p = 0.039). The survival benefit after chemotherapy was dependent on RAB27B expression status: only the subgroup of patients with high RAB27B expression benefited from adjuvant chemotherapy (p = 0.006), but not the subgroup with low RAB27B expression (p = 0.59). Patients with high RAB27B expression who did not receive adjuvant chemotherapy showed a trend towards worse survival compared to the other subgroups. This difference was abolished after treatment with adjuvant chemotherapy. CONCLUSION: These results suggest that RAB27B expression in pancreatic cancer might identify a subgroup of patients with poor survival who might respond well to adjuvant chemotherapy. If resectable, these patients could be considered for neoadjuvant chemotherapy to minimize the risk of not receiving adjuvant chemotherapy. Further prospective studies are needed to confirm these findings. Show more

Keywords: Exosomes, RAB27B, pancreatic cancer, chemotherapy, treatment response

DOI: 10.3233/CBM-220460

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 207-215, 2023

Authors: Yoshikawa, Nobuhisa | Yoshida, Kosuke | Liu, Wenting | Matsukawa, Tetsuya | Hattori, Satomi | Yoshihara, Masato | Tamauchi, Satoshi | Ikeda, Yoshiki | Yokoi, Akira | Shimizu, Yusuke | Niimi, Kaoru | Kajiyama, Hiroaki

Article Type: Research Article

Abstract: BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors …and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer. Show more

Keywords: Endometrial cancer, DDIT4, HIF1A, hypoxia, RNA-seq

DOI: 10.3233/CBM-220368

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 217-225, 2023

Authors: Restrepo-Rodríguez, Luisa | Prada-Arismendy, Jeanette | Castillo, Erwing | Rothlisberger, Sarah

Article Type: Research Article

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a malignant disorder of hematopoietic stem and progenitor cells, characterized by accumulation of immature blasts in the bone marrow and peripheral blood of affected patients. Response to chemotherapy treatment in patients with AML is wide-ranging, and to date there are no adequate molecular biomarkers used to predict clinical outcome. OBJECTIVE: The aim of this study was to identify potential protein biomarkers which could help predict response to induction treatment in AML patients. METHODS: Peripheral blood samples were obtained from 15 AML patients both before and after treatment. …A comparative proteomic analysis was performed using 2D gel electrophoresis followed by Mass Spectrometry. RESULTS: This comparative proteomic study, combined with a protein network analysis, revealed several proteins that could be considered potential biomarkers of poor prognosis in AML: GAPDH which favors increased glucose metabolism; eEF1A1 and Annexin A1 that promote proliferation and migration, cofilin 1 which plays a role in the activation of apoptosis; and GSTP1 which is involved in the processes of detoxification and chemoresistance. CONCLUSIONS: This study gives an insight into a panel of protein biomarkers with prognostic potential that should be further investigated. Show more

Keywords: Acute myeloid leukemia, induction therapy, prognosis, proteomics, two-dimensional gel electrophoresis

DOI: 10.3233/CBM-210540

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 227-235, 2023

Authors: Anzinger, Isabel | Nagel, Dorothea | De Toni, Enrico N. | Ofner, Andrea | Philipp, Alexander B. | Holdt, Lesca M. | Teupser, Daniel | Kolligs, Frank T. | Herbst, Andreas

Article Type: Research Article

Abstract: BACKGROUND: Carcinoembryonic antigen (CEA) is the only established serum biomarker for colorectal cancer (CRC). To facilitate therapy decisions and improve the overall survival of CRC patients, prognostic biomarkers are required. OBJECTIVE: We studied the prognostic value of five different cell free circulating DNA (fcDNA) fragments. The potential markers were ALU115, ALU247, LINE1-79, LINE1-300 and ND1-mt. METHODS: The copy numbers of the DNA fragments were measured in the peripheral blood serum of 268 CRC patients using qPCR, the results were compared to common and previously described markers. RESULTS: We found …that ALU115 and ALU247 fcDNA levels correlate significantly with several clinicopathological parameters. An increased amount of ALU115 and ALU247 fcDNA fragments coincides with methylation of HPP1 (P < 0.001; P < 0.01), which proved to be a prognostic marker itself in former studies and also with increased CEA level (both P < 0.001). ALU115 and ALU247 can define patients with poor survival in UICC stage IV (ALU115: HR = 2.9; 95% Cl 1.8–4.8, P < 0.001; ALU247: HR = 2.2; 95% Cl 1.3–3.6; P = 0.001). Combining ALU115 and HPP1, the prognostic value in UICC stage IV is highly significant (P < 0.001). CONCLUSIONS: This study shows that an increased level of ALU fcDNA is an independent prognostic biomarker for advanced colorectal cancer disease. Show more

Keywords: Colorectal cancer, biomarkers, fcDNA, prognosis, ALU repeats

DOI: 10.3233/CBM-210536

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 237-248, 2023

Authors: Zhang, Junkai | Yang, Yingyu | Wei, Ying | Li, Lamei | Wang, Xinyi | Ye, Zhihua

Article Type: Research Article

Abstract: BACKGROUND: Non-small cell lung cancer (NSCLC) is the most commonly diagnosed solid tumor. Natural killer (NK) cell-based immunotherapy is a promising anti-tumor strategy in various cancers including NSCLC. OBJECTIVE: We aimed to investigate the specific mechanisms that regulate the killing effect of NK cells to NSCLC cells. METHODS: Reverse transcription-quantitative PCR (RT-qPCR) assay was applied to measure the levels of hsa-microRNA (miR)-301a-3p and Runt-related transcription factor 3 (RUNX3). Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of IFN-γ and TNF-α . Lactate dehydrogenase assay was applied to detect …the killing effect of NK cells. Dualluciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to confirm the regulatory relationship between hsa-miR-301a-3p and RUNX3. RESULTS: A low expression of hsa-miR-301a-3p was observed in NK cells stimulated by IL-2. The levels of IFN-γ and TNF-α were increased in NK cells of the IL-2 group. Overexpression of hsa-miR-301a-3p reduced the levels of IFN-γ and TNF-α as well as the killing effect of NK cells. Furthermore, RUNX3 was identified to be a target of hsamiR-301a-3p. hsa-miR-301a-3p suppressed the cytotoxicity of NK cells to NSCLC cells by inhibiting the expression of RUNX3. We found hsa-miR-301a-3p promoted tumor growth by suppressing the killing effect of NK cells against NSCLC cells in vivo . CONCLUSIONS: Hsa-miR-301a-3p suppressed the killing effect of NK cells on NSCLC cells by targeting RUNX3, which may provide promising strategies for NK cell-based antitumor therapies. Show more

Keywords: Non-small cell lung cancer, hsa-miR-301a-3p, killing effect, natural killer cells, RUNX3

DOI: 10.3233/CBM-220469

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 249-259, 2023

Authors: Chen, Huaqiu | Xie, Huanyu | Zhang, Yuanyuan | Wang, Guangming

Article Type: Research Article

Abstract: BACKGROUND: Cervical cancer (CC) is a malignant tumor threatening women’s health. Replication factor C (RFC) 5 is significantly highly expressed in CC tissues, and the immune microenvironment plays a crucial role in tumor initiation, progression, and metastasis. OBJECTIVE: To determine the prognostic role of RFC5 in CC, analyze the immune genes significantly associated with RFC5 , and establish a nomogram to evaluate the prognosis of patients with CC. METHODS: High RFC5 expression in patients with CC was analyzed and verified through TCGA GEO, TIMER2.0, and HPA databases. A risk score model …was constructed using RFC5 -related immune genes identified using R packages. Combining the risk score model and clinical information of patients with CC, a nomogram was constructed to evaluate the prognosis of patients with CC. RESULTS: Comprehensive analysis showed that the risk score was a prognostic factor for CC. The nomogram could predict the 3-year overall survival of patients with CC. CONCLUSIONS: RFC5 was validated as a biomarker for CC. The RFC5 related immune genes were used to establish a new prognostic model of CC. Show more

Keywords: Cervical cancer, risk score, prognostic signature, immunoinhibitors, immunostimulators

DOI: 10.3233/CBM-220347

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 261-277, 2023

Authors: Huang, Anzhong | Qin, Chunzhi | Wu, Mengting | Zhang, Dawei | Wu, Guangbin | Sun, Peilong

Article Type: Research Article

Abstract: BACKGROUND: The role of ELAPOR1 has been evaluated in several cancers but has not been elucidated in colorectal cancer (CRC). OBJECTIVE: To investigate the role of ELAPOR1 in CRC. METHODS: In the present study, the correlation between ELAPOR1 and survival of CRC patients in TCGA-COAD-READ datasets was predicted, and the difference in ELAPOR1 expression between tumor and normal tissues was analyzed. ELAPOR1 expression in CRC tissues was measured by immunohistochemistry. Then, ELAPOR1 and ELAPOR1-shRNA plasmids were constructed and transfected into SW620 and RKO cells. The effects were assessed by CCK-8, colony formation, transwell, and …wound healing assays. Transcriptome sequencing and bioinformatics analysis were performed on the genes before and after ELAPOR1 overexpression in SW620 cells; the differentially expressed genes were substantiated by real-time quantitative reverse transcription PCR. RESULTS: High level of ELAPOR1 is associated with favorable disease-free survival and overall survival. Compared to normal mucosa, ELAPOR1 is lower in CRC. Moreover, ELAPOR1 overexpression significantly inhibits cell proliferation and invasion in vitro in SW260 and RKO cells. Conversely, ELAPOR1-shRNA promotes CRC cell proliferation and invasion. Among the 355 differentially expressed mRNAs identified, 234 were upregulated and 121 were downregulated. Bioinformatics indicated that these genes are involved in receptor binding, plasma membrane, negative regulation of cell proliferation, as well as common cancer signaling pathways. CONCLUSIONS: ELAPOR1 plays an inhibitory role in CRC and may be used as a prognostic indicator and a potential target for treatment. Show more

Keywords: ELAPOR1, prognosis, proliferation, invasion, colorectal cancer

DOI: 10.3233/CBM-220285

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 279-288, 2023

Authors: Cao, Bing | Yang, Siyu | Yan, Lailai | Li, Nan

Article Type: Research Article

Abstract: BACKGROUND: Breast cancer is the most worldwide commonly found malignancy among women. The evidence for lipidomic studies of breast cancer in the Chinese population is relatively limited. OBJECTIVE: Our current study aimed to identify peripheral lipids capable of distinguishing adults with and without malignant breast cancer in a Chinese population and to explore the potential lipid metabolism pathways implicated in breast cancer. METHODS: Lipidomics was performed with an Ultimate 3000 UHPLC system coupled with a Q-Exactive HF MS platform by using the serum of 71 female patients with malignant breast cancer and 92 …age-matched (± 2 years) healthy women. The data were uploaded to and processed by the specialized online software Metaboanalyst 5.0. Both univariate and multivariate analyses were carried out for potential biomarker screening. Areas under the receiver-operating characteristic (ROC) curves (AUCs) of identified differential lipids were obtained for evaluating their classification capacity. RESULTS: A total of 47 significantly different lipids were identified by applying the following criteria: false discovery rate-adjusted P < 0.05, variable importance in projection ⩾ 1.0, and fold change ⩾ 2.0 or ⩽ 0.5. Among them, 13 lipids were identified as diagnostic biomarkers with the area under curve (AUC) greater than 0.7. Multivariate ROC curves indicated that AUCs greater than 0.8 could be achieved with 2–47 lipids. CONCLUSIONS: Using an untargeted LC-MS-based metabolic profiling approach, our study provides preliminary evidence that extensive dysregulations of OxPCs, PCs, SMs and TAGs were involved in the pathological processes of breast cancer. We provided clues for furtherly investigating the role of lipid alterations in the pathoetiology of breast cancer. Show more

Keywords: Lipidomics, breast cancer, biomarker, LC-MS, metabolism

DOI: 10.3233/CBM-220462

Citation: Cancer Biomarkers, vol. 37, no. 4, pp. 289-297, 2023