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Advanced Research on Biomarkers in Gastrointestinal Cancer
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Advanced Research on Biomarkers in Gastrointestinal Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 12006

Special Issue Editor

Prof. Dr. Simona Gurzu

E-Mail Website
Guest Editor
Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Science and Technology, 38 Gheorghe Marinescu Street, 540139 Targu Mures, Romania
Interests: oncopathology; gastric cancer; colorectal cancer; hepatocellular carcinoma; epithelial–mesenchymal transition; targeted therapy of cancer; histopathology; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The scope of this Special Issue is to collect papers referring to biomarkers involved in the genesis, evolution, and systemic or lymphatic spread of gastrointestinal cancer. As, nowadays, targeted therapy is a hot issue, the identification of new predictive biomarkers has become mandatory in clinical practice. Any research or review-type papers that include data about tumor biomarkers, from experimental studies to clinical trials, are welcome. If some papers are mainly based on in silico analyses or examinations of public gene databases, they should include external validations of their own cohorts. We expect to receive papers focused on tissue or serum biomarkers, from protein expression to gene mutations and circulating DNA. Your individual contribution might be a step towards a better life for oncologic patients.

Prof. Dr. Simona Gurzu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • serum biomarkers
  • circulating DNA
  • microRNAs
  • tumor tissue
  • individualized therapy
  • gene profile
  • oncology
  • pathology
  • gastric cancer
  • colorectal cancer
  • esophageal cancer
  • carcinogenesis in oral mucosa
  • hepatocellular carcinoma
  • cholangiocarcinoma
  • pancreatic cancer
  • familial cancer

Published Papers (9 papers)

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Research

Jump to: Review, Other

24 pages, 11496 KiB  
Article
Glutaredoxin 2 Protein (Grx2) as an Independent Prognostic Factor Associated with the Survival of Colon Adenocarcinoma Patients
by Marlena Brzozowa-Zasada, Adam Piecuch, Karolina Bajdak-Rusinek, Karolina Gołąbek, Marek Michalski, Kamil Janelt and Natalia Matysiak
Int. J. Mol. Sci. 2024, 25(2), 1060; https://doi.org/10.3390/ijms25021060 - 15 Jan 2024
Viewed by 970
Abstract
Glutaredoxin 2 (Grx2; Glrx2) is a glutathione-dependent oxidoreductase located in mitochondria, which is central to the regulation of glutathione homeostasis and mitochondrial redox, and plays a crucial role in highly metabolic tissues. In response to mitochondrial redox signals and oxidative stress, Grx2 can [...] Read more.
Glutaredoxin 2 (Grx2; Glrx2) is a glutathione-dependent oxidoreductase located in mitochondria, which is central to the regulation of glutathione homeostasis and mitochondrial redox, and plays a crucial role in highly metabolic tissues. In response to mitochondrial redox signals and oxidative stress, Grx2 can catalyze the oxidation and S-glutathionylation of membrane-bound thiol proteins in mitochondria. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of Grx2 protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of Grx2 and tumor histological grade, depth of invasion, regional lymph node involvement, angioinvasion, staging, and PCNA immunohistochemical expression. It was found that 87% of patients with stage I had high levels of Grx2 expression. In contrast, only 33% of patients with stage II and 1% of patients with stage III had high levels of Grx2 expression. Moreover, the multivariate analysis revealed that the immunohistochemical expression of Grx2 protein apart from the grade of tumor differentiation was an independent prognostic factors for the survival of patients with colon adenocarcinoma. Studies analyzing Grx2 levels in patients’ blood confirmed that the highest levels of serum Grx2 protein was also found in stage I patients, which was reflected in the survival curves. A higher level of Grx2 in the serum has been associated with a more favorable outcome. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western Blot. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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14 pages, 1953 KiB  
Communication
Influence of Clinical Factors on miR-3613-3p Expression in Colorectal Cancer
by Paulina Gil-Kulik, Alicja Petniak, Natalia Kluz, Grzegorz Wallner, Tomasz Skoczylas, Aleksander Ciechański and Janusz Kocki
Int. J. Mol. Sci. 2023, 24(18), 14023; https://doi.org/10.3390/ijms241814023 - 13 Sep 2023
Viewed by 873
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death globally. Because of a tendency to be an asymptomatic primary tumor and therefore resulting in late detection, most CRC patients are diagnosed in the advanced stage. Several miRNAs have the potential [...] Read more.
Colorectal cancer (CRC) is the second most common cause of cancer-related death globally. Because of a tendency to be an asymptomatic primary tumor and therefore resulting in late detection, most CRC patients are diagnosed in the advanced stage. Several miRNAs have the potential to become novel noninvasive biomarkers measured as diagnostic and prognostic indicators of CRC to guide surgical therapies and promote the understanding of the carcinogenesis of CRC. Since the change of miR-3613-3p was associated with several types of cancer other than colorectal cancer, there is a lack of functional evidence and the results are inconsistent. We conducted a pilot microarray study in which we noted a decreased expression of miR-3613-3p in colorectal cancer cells, then we confirmed the expression of miR-3613-3p by qPCR on a group of 83 patients, including 65 patients with colorectal cancer, 5 with a benign tumor and 13 from the control group. We noted that in both malignant and benign tumors, miR-3613-3p is downgraded relative to the surrounding tissue. As a result of the study, we also observed colorectal tumor tissue and surrounding tissue in patients with colorectal cancer who received radiotherapy before surgery, which showed a significantly higher expression of miR-3613-3p compared to patients who did not receive radiotherapy. In addition, we noted that the tissue surrounding the tumor in patients with distant metastases showed a significantly higher expression of miR-3613-3p compared to patients without distant metastases. The increased expression of miR-3613-3p in patients after radiotherapy suggests the possibility of using this miR as a therapeutic target for CRC, but this requires confirmation in further studies. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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17 pages, 7497 KiB  
Article
CXCR4 Expressed by Tumor-Infiltrating B Cells in Gastric Cancer Related to Survival in the Tumor Microenvironment: An Analysis Combining Single-Cell RNA Sequencing with Bulk RNA Sequencing
by Chen Su, Rong Yu, Xiaoquan Hong, Panpan Zhang, Yingying Guo, Jian-Chun Cai and Jingjing Hou
Int. J. Mol. Sci. 2023, 24(16), 12890; https://doi.org/10.3390/ijms241612890 - 17 Aug 2023
Cited by 2 | Viewed by 1742
Abstract
According to the World Health Organization (WHO), gastric cancer (GC) is the fourth leading cause of tumor-related mortality globally and one of the most prevalent malignant tumors. To better understand the role of tumor-infiltrating B cells (TIBs) in GC, this work used single-cell [...] Read more.
According to the World Health Organization (WHO), gastric cancer (GC) is the fourth leading cause of tumor-related mortality globally and one of the most prevalent malignant tumors. To better understand the role of tumor-infiltrating B cells (TIBs) in GC, this work used single-cell RNA sequencing (scRNA-Seq) and bulk RNA sequencing (bulk RNA-Seq) data to identify candidate hub genes. Both scRNA-Seq and bulk RNA-Seq data for stomach adenocarcinoma (STAD) were obtained from the GEO and TCGA databases, respectively. Using scRNA-seq data, the FindNeighbors and FindClusters tools were used to group the cells into distinct groups. Immune cell clusters were sought in the massive RNA-seq expression matrix using the single-sample gene set enrichment analysis (ssGSEA). The expression profiles were used in Weighted Gene Coexpression Network Analysis (WGCNA) to build TCGA’s gene coexpression networks. Next, univariate Cox regression, LASSO regression, and Kaplan–Meier analyses were used to identify hub genes in scRNA-seq data from sequential B-cell analyses. Finally, we examined the correlation between the hub genes and TIBs utilizing the TISIDB database. We confirmed the immune-related markers in clinical validation samples using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). 15 cell clusters were classified in the scRNA-seq database. According to the WGCNA findings, the green module is most associated with cancer and B cells. The intersection of 12 genes in two separate datasets (scRNA and bulk) was attained for further analysis. However, survival studies revealed that increased C-X-C motif chemokine receptor 4 (CXCR4) expression was linked to worse overall survival. CXCR4 expression is correlated with active, immature, and memory B cells in STAD were identified. Finally, RT-PCR and IHC assays verified that in GC, CXCR4 is overexpressed, and its expression level correlates with TIBs. We used scRNA-Seq and bulk RNA-Seq to study STAD’s cellular composition. We found that CXCR4 is highly expressed by TIBs in GC, suggesting that it may serve as a hub gene for these cells and a starting point for future research into the molecular mechanisms by which these immune cells gain access to tumors and potentially identify therapeutic targets. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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16 pages, 497 KiB  
Article
Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania
by Vlad-Adrian Afrăsânie, Mihai-Vasile Marinca, Bogdan Gafton, Teodora Alexa-Stratulat, Alexandra Rusu, Eliza-Maria Froicu, Daniel Sur, Cristian Virgil Lungulescu, Larisa Popovici, Andrei-Vlad Lefter, Irina Afrăsânie, Anca-Viorica Ivanov, Lucian Miron and Cristina Rusu
Int. J. Mol. Sci. 2023, 24(16), 12679; https://doi.org/10.3390/ijms241612679 - 11 Aug 2023
Cited by 4 | Viewed by 1225
Abstract
Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania [...] Read more.
Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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Review

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14 pages, 604 KiB  
Review
Clinical Application of Liquid Biopsy in Pancreatic Cancer: A Narrative Review
by Elena Ramírez-Maldonado, Sandra López Gordo, Rui Pedro Major Branco, Mihai-Calin Pavel, Laia Estalella, Erik Llàcer-Millán, María Alejandra Guerrero, Estrella López-Gordo, Robert Memba and Rosa Jorba
Int. J. Mol. Sci. 2024, 25(3), 1640; https://doi.org/10.3390/ijms25031640 - 29 Jan 2024
Viewed by 1105
Abstract
Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient [...] Read more.
Pancreatic ductal adenocarcinoma contributes significantly to global cancer-related deaths, featuring only a 10% survival rate over five years. The quest for novel tumor markers is critical to facilitate early diagnosis and tailor treatment strategies for this disease, which is key to improving patient outcomes. In pancreatic ductal adenocarcinoma, these markers have been demonstrated to play a crucial role in early identification, continuous monitoring, and prediction of its prognosis and have led to better patient outcomes. Nowadays, biopsy specimens serve to ascertain diagnosis and determine tumor type. However, liquid biopsies present distinct advantages over conventional biopsy techniques. They offer a noninvasive, easily administered procedure, delivering insights into the tumor’s status and facilitating real-time monitoring. Liquid biopsies encompass a variety of elements, such as circulating tumor cells, circulating tumor DNA, extracellular vesicles, microRNAs, circulating RNA, tumor platelets, and tumor endothelial cells. This review aims to provide an overview of the clinical applications of liquid biopsy as a technique in the management of pancreatic cancer. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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17 pages, 2925 KiB  
Review
Combinatorial Gene Expression Profiling of Serum HULC, HOTAIR, and UCA1 lncRNAs to Differentiate Hepatocellular Carcinoma from Liver Diseases: A Systematic Review and Meta-Analysis
by Lalita Lumkul, Phatcharida Jantaree, Kritsada Jaisamak, Wasinee Wongkummool, Worakitti Lapisatepun, Santhasiri Orrapin, Sasimol Udomruk, Luca Lo Piccolo and Parunya Chaiyawat
Int. J. Mol. Sci. 2024, 25(2), 1258; https://doi.org/10.3390/ijms25021258 - 19 Jan 2024
Viewed by 1083
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited early detection methods, primarily relying on conventional approaches like imaging and alpha-fetoprotein (AFP). Although non-coding RNAs (ncRNAs) show promise as potential biomarkers in HCC, their true utility remains uncertain. We conducted [...] Read more.
Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited early detection methods, primarily relying on conventional approaches like imaging and alpha-fetoprotein (AFP). Although non-coding RNAs (ncRNAs) show promise as potential biomarkers in HCC, their true utility remains uncertain. We conducted a comprehensive review of 76 articles, analyzing 88 circulating lncRNAs in 6426 HCC patients. However, the lack of a standardized workflow protocol has hampered holistic comparisons across the literature. Consequently, we herein confined our meta-analysis to only a subset of these lncRNAs. The combined analysis of serum highly upregulated in liver cancer (HULC) gene expression with homeobox transcript antisense intergenic RNA (HOTAIR) and urothelial carcinoma-associated 1 (UCA1) demonstrated markedly enhanced sensitivity and specificity in diagnostic capability compared to traditional biomarkers or other ncRNAs. These findings could have substantial implications for the early diagnosis and tailored treatment of HCC. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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16 pages, 1797 KiB  
Review
The Use of ctDNA in the Diagnosis and Monitoring of Hepatocellular Carcinoma—Literature Review
by Agnieszka Kopystecka, Rafał Patryn, Magdalena Leśniewska, Julia Budzyńska and Ilona Kozioł
Int. J. Mol. Sci. 2023, 24(11), 9342; https://doi.org/10.3390/ijms24119342 - 26 May 2023
Cited by 4 | Viewed by 1799
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important limitations, especially in very small nodules and those which show atypical imaging features. In recent years, liquid biopsy and molecular analysis of tumor breakdown products have become an attractive source of new biomarkers. Patients with liver and biliary malignancies, including hepatocellular carcinoma (HCC), may greatly benefit from ctDNA testing. These patients are often diagnosed at an advanced stage of the disease, and relapses are common. Molecular analysis may indicate the best cancer treatment tailored to particular patients with specific tumor DNA mutations. Liquid biopsy is a minimally invasive technique that facilitates the early detection of cancer. This review summarizes the knowledge of ctDNA in liquid biopsy as an indicator for early diagnosis and monitoring of hepatocellular cancer. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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Other

Jump to: Research, Review

12 pages, 695 KiB  
Systematic Review
Metabolic Signatures: Pioneering the Frontier of Rectal Cancer Diagnosis and Response to Neoadjuvant Treatment with Biomarkers—A Systematic Review
by Răzvan Alexandru Ciocan, Andra Ciocan, Florin Vasile Mihăileanu, Cristina-Paula Ursu, Ștefan Ursu, Cătălin Bodea, Ariana-Anamaria Cordoș, Bogdan Augustin Chiș, Nadim Al Hajjar, Noemi Dîrzu and Dan-Sebastian Dîrzu
Int. J. Mol. Sci. 2024, 25(4), 2381; https://doi.org/10.3390/ijms25042381 - 17 Feb 2024
Viewed by 860
Abstract
Colorectal cancer (CRC) is one of the most aggressive, heterogenous, and fatal types of human cancer for which screening, and more effective therapeutic drugs are urgently needed. Early-stage detection and treatment greatly improve the 5-year survival rate. In the era of targeted therapies [...] Read more.
Colorectal cancer (CRC) is one of the most aggressive, heterogenous, and fatal types of human cancer for which screening, and more effective therapeutic drugs are urgently needed. Early-stage detection and treatment greatly improve the 5-year survival rate. In the era of targeted therapies for all types of cancer, a complete metabolomic profile is mandatory before neoadjuvant therapy to assign the correct drugs and check the response to the treatment given. The aim of this study is to discover specific metabolic biomarkers or a sequence of metabolomic indicators that possess precise diagnostic capabilities in predicting the efficacy of neoadjuvant therapy. After searching the keywords, a total of 108 articles were identified during a timeframe of 10 years (2013–2023). Within this set, one article was excluded due to the use of non-English language. Six scientific papers were qualified for this investigation after eliminating all duplicates, publications not referring to the subject matter, open access restriction papers, and those not applicable to humans. Biomolecular analysis found a correlation between metabolomic analysis of colorectal cancer samples and poor progression-free survival rates. Biomarkers are instrumental in predicting a patient’s response to specific treatments, guiding the selection of targeted therapies, and indicating resistance to certain drugs. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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9 pages, 1110 KiB  
Case Report
Signet-Ring Cell Squamous Cell Carcinoma: A Biphenotypic Neoplasm of the Gastro-Esophageal Junction with Uncertain Biological Potential: Case Report and Literature Review
by Catalin Bogdan Satala, Zsolt Kovacs, Tivadar Bara, Jr., Ioan Jung and Simona Gurzu
Int. J. Mol. Sci. 2023, 24(11), 9535; https://doi.org/10.3390/ijms24119535 - 31 May 2023
Cited by 1 | Viewed by 1774
Abstract
The signet-ring cell variant of squamous cell carcinoma (SCC) is an extremely rare histological subtype, with only 24 cases (including the present case) reported in the Medline database: 15 affecting the external surface of the body, 3 in the lung, 2 affecting the [...] Read more.
The signet-ring cell variant of squamous cell carcinoma (SCC) is an extremely rare histological subtype, with only 24 cases (including the present case) reported in the Medline database: 15 affecting the external surface of the body, 3 in the lung, 2 affecting the uterine cervix, 1 involving the gingiva, another one affecting the esophagus and the present case that is the first reported at the gastro-esophageal junction (GEJ). In one case, the location of the lesion was not mentioned. A 59-year-old male patient underwent segmental eso-gastrectomy for carcinoma of the GEJ. The microscopic examination showed a pT3N1-staged SCC composed of solid nests admixed in over 30% of the tumor, with cells having eccentrically located nuclei and clear vacuolated cytoplasm. The signet-ring cells did not show mucinous secretion and were positive for keratin 5/6 and vimentin, with nuclear expression of β-catenin and Sox2 and focal membrane positivity for E-cadherin. Based on these features, the case was considered a signet-ring SCC with epithelial–mesenchymal transition. Thirty-one months after surgery, the patient was disease-free, with no local recurrence and no known distant metastases. In SCC, a signet-ring cell component might be an indicator of the dedifferentiation of tumor cells towards a mesenchymal molecular subtype. Full article
(This article belongs to the Special Issue Advanced Research on Biomarkers in Gastrointestinal Cancer)
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