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16 pages, 4327 KiB

Open AccessArticle

Elevated Serum Gastrin Is Associated with Melanoma Progression: Putative Role in Increased Migration and Invasion of Melanoma Cells

by Akos Janos Varga, Istvan Balazs Nemeth, Lajos Kemeny, Janos Varga, Laszlo Tiszlavicz, Dinesh Kumar, Steven Dodd, Alec W. M. Simpson, Tunde Buknicz, Rob Beynon, Deborah Simpson, Tibor Krenacs, Graham J. Dockray and Andrea Varro

Int. J. Mol. Sci. 2023, 24(23), 16851; https://doi.org/10.3390/ijms242316851 - 28 Nov 2023

Viewed by 1440

Abstract

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis [...] Read more.

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III–IV than stage I–II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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22 pages, 4375 KiB

Open AccessArticle

Proteomics Profiling of Bladder Cancer Tissues from Early to Advanced Stages Reveals NNMT and GALK1 as Biomarkers for Early Detection and Prognosis of BCa

by Katarina Davalieva, Sanja Kiprijanovska, Ognen Ivanovski, Aleksandar Trifunovski, Skender Saidi, Aleksandar Dimovski and Zivko Popov

Int. J. Mol. Sci. 2023, 24(19), 14938; https://doi.org/10.3390/ijms241914938 - 6 Oct 2023

Cited by 1 | Viewed by 2148

Abstract

The high recurrence rate and invasive diagnostic and monitoring methods in bladder cancer (BCa) clinical management require the development of new non-invasive molecular tools for early detection, particularly for low-grade and low-stage BCa as well as for risk stratification. By using an in-solution [...] Read more.

The high recurrence rate and invasive diagnostic and monitoring methods in bladder cancer (BCa) clinical management require the development of new non-invasive molecular tools for early detection, particularly for low-grade and low-stage BCa as well as for risk stratification. By using an in-solution digestion method and label-free data-independent LC-MS/MS coupled with ion mobility, we profiled the BCa tissues from initiation to advanced stages and confidently identified and quantified 1619 proteins (≥2 peptides). A statistically significant difference in abundance (Anova ≤ 0.05) showed 494 proteins. Significant correlation with stage with steady up or down with BCa stages showed 15 proteins. Testing of NNMT, GALK1, and HTRA1 in urine samples showed excellent diagnostic potential for NNMT and GALK1 with AUC of 1.000 (95% CI: 1.000–1.000; p < 0.0001) and 0.801 (95% CI: 0.655–0.947; p < 0.0001), respectively. NNMT and GALK1 also showed very good potential in discriminating non-invasive low-grade from invasive high-grade BCa with AUC of 0.763 (95% CI: 0.606–0.921; p = 0.001) and 0.801 (95% CI: 0.653–0.950; p < 0.0001), respectively. The combination of NNMT and GALK1 increased prognostic accuracy (AUC = 0.813). Our results broaden the range of potential novel candidates for non-invasive BCa diagnosis and prognosis. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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18 pages, 9676 KiB

Open AccessArticle

Establishment of a Seven-Gene Signature Associated with CD8⁺ T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma

by Yubin Chen, Xinyu Zhou, Yanwei Xie, Jianan Wu, Tingting Li, Tian Yu, Yipeng Pang and Wenlong Du

Int. J. Mol. Sci. 2023, 24(18), 13729; https://doi.org/10.3390/ijms241813729 - 6 Sep 2023

Cited by 3 | Viewed by 2498

Abstract

Tumor immune microenvironment constituents, such as CD8⁺ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be [...] Read more.

Tumor immune microenvironment constituents, such as CD8⁺ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8⁺ T cells. The differentially expressed genes (DEGs) linked to CD8⁺ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8⁺ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8⁺ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8⁺ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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14 pages, 690 KiB

Open AccessArticle

Expression of Immune-Related and Inflammatory Markers and Their Prognostic Impact in Colorectal Cancer Patients

by Sanghyun An, Soo-Ki Kim, Hye Youn Kwon, Cheol Su Kim, Hui-Jae Bang, Hyejin Do, BoRa Kim, Kwangmin Kim and Youngwan Kim

Int. J. Mol. Sci. 2023, 24(14), 11579; https://doi.org/10.3390/ijms241411579 - 18 Jul 2023

Cited by 4 | Viewed by 1841

Abstract

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues [...] Read more.

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues and to investigate whether they are related to the clinicopathological features and prognosis of CRC. Seventy patients with CRC who underwent curative surgical resection between December 2014 and January 2017 were included in this study. Tissue samples were obtained from tumor and non-tumor areas in the patients’ colons. The concentrations of immune-related markers (APRIL/TNFSF13, BAFF, LAG-3, PD-1, PD-L1, and CTLA-4) and inflammatory markers (CHIT, MMP-3, osteocalcin, pentraxin-3, sTNF-R1, and sTNF-R2) in the samples were measured using the Bio-plex Multiplex Immunoassay system. The concentrations of APRIL/TNFSF13, BAFF, and MMP-3 in the samples were significantly high; thus, we conducted analyses based on the cut-off values for these three markers. The high-APRIL/TNFSH13-expression group showed a significantly higher rate of metastatic lesions than the low-expression group, whereas the high-MMP-3-expression group had higher CEA levels, more lymph node metastases, and more advanced disease stages than the low-expression group. The five-year disease-free survival of the high-MMP-3-expression group was significantly shorter than that of the low-expression group (65.1% vs. 90.2%, p = 0.033). This study provides evidence that the APRIL/TNFSF13, BAFF, and MMP-3 pathway is overexpressed in CRC tissues and is associated with unfavorable clinicopathological features and poor prognosis in CRC patients. These markers could serve as diagnostic or prognostic biomarkers for CRC. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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21 pages, 2816 KiB

Open AccessArticle

Spatially Resolved Proteomic and Transcriptomic Profiling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter- and Intratumoral Heterogeneity

by Beáta Szeitz, Tibor Glasz, Zoltán Herold, Gábor Tóth, Mirjam Balbisi, János Fillinger, Szabolcs Horváth, Réka Mohácsi, Ho Jeong Kwon, Judit Moldvay, Lilla Turiák and Attila Marcell Szász

Int. J. Mol. Sci. 2023, 24(14), 11369; https://doi.org/10.3390/ijms241411369 - 12 Jul 2023

Cited by 2 | Viewed by 2269

Abstract

Pulmonary adenocarcinomas (pADCs) with an ALK rearrangement are a rare cancer subtype, necessitating comprehensive molecular investigations to unravel their heterogeneity and improve therapeutic strategies. In this pilot study, we employed spatial transcriptomic (NanoString GeoMx) and proteomic profiling to investigate seven treatment-naïve pADCs with [...] Read more.

Pulmonary adenocarcinomas (pADCs) with an ALK rearrangement are a rare cancer subtype, necessitating comprehensive molecular investigations to unravel their heterogeneity and improve therapeutic strategies. In this pilot study, we employed spatial transcriptomic (NanoString GeoMx) and proteomic profiling to investigate seven treatment-naïve pADCs with an ALK rearrangement. On each FFPE tumor slide, 12 smaller and 2–6 larger histopathologically annotated regions were selected for transcriptomic and proteomic analysis, respectively. The correlation between proteomics and transcriptomics was modest (average Pearson’s r = 0.43 at the gene level). Intertumoral heterogeneity was more pronounced than intratumoral heterogeneity, and normal adjacent tissue exhibited distinct molecular characteristics. We identified potential markers and dysregulated pathways associated with tumors, with a varying extent of immune infiltration, as well as with mucin and stroma content. Notably, some markers appeared to be specific to the ALK-driven subset of pADCs. Our data showed that within tumors, elements of the extracellular matrix, including FN1, exhibited substantial variability. Additionally, we mapped the co-localization patterns of tumor microenvironment elements. This study represents the first spatially resolved profiling of ALK-driven pADCs at both the gene and protein expression levels. Our findings may contribute to a better understanding of this cancer type prior to treatment with ALK inhibitors. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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17 pages, 10528 KiB

Open AccessArticle

Characterization of the Clinical Significance and Immunological Landscapes of a Novel TMEMs Signature in Hepatocellular Carcinoma and the Contribution of TMEM201 to Hepatocarcinogenesis

by Desheng Chen, Yichao Lou, Jing Lu, Xuhui Fan, Qi Zhu and Hongcheng Sun

Int. J. Mol. Sci. 2023, 24(12), 10285; https://doi.org/10.3390/ijms241210285 - 17 Jun 2023

Cited by 3 | Viewed by 1913

Abstract

Aberrant transmembrane protein (TMEM) expression is implicated in tumor progression, but its functional role in hepatocellular carcinoma (HCC) is unclear. Thus, we aim to characterize the functional contributions of TMEM in HCC. In this study, four novel TMEM-family genes (TMEMs), TMEM106C, TMEM201, TMEM164, [...] Read more.

Aberrant transmembrane protein (TMEM) expression is implicated in tumor progression, but its functional role in hepatocellular carcinoma (HCC) is unclear. Thus, we aim to characterize the functional contributions of TMEM in HCC. In this study, four novel TMEM-family genes (TMEMs), TMEM106C, TMEM201, TMEM164, and TMEM45A, were screened to create a TMEMs signature. These candidate genes are distinguished between patients with varying survival statuses. High-risk HCC patients had a significantly worse prognosis and more advanced clinicopathological characteristics in both the training and validation groups. The GO and KEGG analyses unveiled that the TMEMs signature might play a crucial role in cell-cycle-relevant and immune-related pathways. We found that the high-risk patients had lower stromal scores and a more immunosuppressive tumor microenvironment with massive infiltration of macrophages and Treg cells, whereas the low-risk group had higher stromal scores and gamma delta T-cell infiltration. Moreover, the expression level of suppressive immune checkpoints increased as the TMEM-signature scores increased. Furthermore, the in vitro experiments validated TMEM201, one feature of the TMEMs signature, and facilitated HCC proliferation, survival, and migration. The TMEMs signature provided a more precise prognostic evaluation of HCC and reflected the immunological status of HCC. Of the TMEMs signature studied, TMEM201 was found to significantly promote HCC progression. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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16 pages, 3923 KiB

Open AccessArticle

Alterations of miRNA Expression in Diffuse Hyperplastic Perilobar Nephroblastomatosis: Mapping the Way to Understanding Wilms’ Tumor Development and Differential Diagnosis

by Ádám Csók, Tamás Micsik, Zsófia Magyar, Tamás Tornóczky, Levente Kuthi, Yumika Nishi, Krisztina Szirák, Monika Csóka, Gábor Ottóffy, Beáta Soltész, István Balogh and Gergely Buglyó

Int. J. Mol. Sci. 2023, 24(10), 8793; https://doi.org/10.3390/ijms24108793 - 15 May 2023

Cited by 2 | Viewed by 1993

Abstract

Wilms’ tumor (WT) is the most common renal malignancy in children. In diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), nephrogenic rests result in a bulky enlargement of the kidney, a condition considered as a premalignant state before WT. Despite relevant clinical differences between WT and [...] Read more.

Wilms’ tumor (WT) is the most common renal malignancy in children. In diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), nephrogenic rests result in a bulky enlargement of the kidney, a condition considered as a premalignant state before WT. Despite relevant clinical differences between WT and DHPLN, they are often challenging to distinguish based on histology. Molecular markers would improve differential diagnosis, but none are available at present. In our study, we investigated the potential of microRNAs (miRNAs) as such biomarkers, also aiming to shed light on the chronological order of expression changes. Formalin-fixed, paraffin-embedded (FFPE) samples from four DHPLN cases and adjacent healthy tissues were tested using a PCR array containing primers for 84 miRNAs implicated in genitourinary cancer. Expression in DHPLN was compared to WT data available in dbDEMC. Let-7, miR-135, miR-146a-5p, miR-182-5p, miR-183-5p, miR-20b-3p, miR-29b-3p, miR-195-5p and miR-17-5p showed potential to be used as biomarkers to distinguish WT and DHPLN in cases when traditional differential diagnosis is inconclusive. Our study also revealed miRNAs which may play a role in the initial steps of the pathogenesis (at a precancerous stage) and ones which become deregulated later in WT. More experiments are needed to confirm our observations and find new candidate markers. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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19 pages, 2384 KiB

Open AccessArticle

Genomic Landscape of Normal and Breast Cancer Tissues in a Hungarian Pilot Cohort

by Orsolya Pipek, Donát Alpár, Orsolya Rusz, Csaba Bödör, Zoltán Udvarnoki, Anna Medgyes-Horváth, István Csabai, Zoltán Szállási, Lilla Madaras, Zsuzsanna Kahán, Gábor Cserni, Bence Kővári, Janina Kulka and Anna Mária Tőkés

Int. J. Mol. Sci. 2023, 24(10), 8553; https://doi.org/10.3390/ijms24108553 - 10 May 2023

Cited by 1 | Viewed by 2811

Abstract

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. [...] Read more.

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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22 pages, 22151 KiB

Open AccessArticle

Systemic Analyses of Cuproptosis-Related lncRNAs in Pancreatic Adenocarcinoma, with a Focus on the Molecular Mechanism of LINC00853

by Leifeng Chen, Lin Zhang, Haihua He, Fei Shao, Yibo Gao and Jie He

Int. J. Mol. Sci. 2023, 24(9), 7923; https://doi.org/10.3390/ijms24097923 - 27 Apr 2023

Cited by 9 | Viewed by 2424

Abstract

Pancreatic cancer (PC) is a deadly malignant digestive tumor with poor prognoses and a lack of effective treatment options. Cuproptosis, a recently identified copper-dependent programmed cell death type, has been implicated in multiple cancers. Long non-coding RNAs (lncRNAs) are also linked to the [...] Read more.

Pancreatic cancer (PC) is a deadly malignant digestive tumor with poor prognoses and a lack of effective treatment options. Cuproptosis, a recently identified copper-dependent programmed cell death type, has been implicated in multiple cancers. Long non-coding RNAs (lncRNAs) are also linked to the progression of PC. However, the role and prognostic values of cuproptosis-related lncRNAs in pancreatic adenocarcinoma (PAAD) remain unclear. In this study, we systemically analyzed the differential expressions and prognostic values of 672 cuproptosis-related lncRNAs in PAAD. Based on this, a prognostic signature including four lncRNAs (LINC00853, AC099850.3, AC010719.1, and AC006504.7) was constructed and was able to divide PAAD patients into high- and low-risk groups with significantly different prognoses. Next, we focused on lncRNA LINC00853. The differential expressions of LINC00853 between normal tissue and PAAD samples were validated by qRT-PCR. LINC00853 was knocked down by siRNA in PC cell lines BxPC-3 and PANC-1 and the oncogenic role of LINC00853 was validated by CCK8, colony formation, and EdU assays. Subsequently, LINC00853 knockdown cells were subjected to tumor xenograft tests and exhibited decreased tumor growth in nude mice. Mechanistically, knockdown of LINC00853 significantly reduced cellular glycolysis and enhanced cellular mitochondrial respiration levels in PC cells. Moreover, knockdown of LINC00853 decreased the protein level of a glycolytic kinase PFKFB3. Finally, glycolysis tests and functional tests using LINC00853 and HA-PFKFB3 indicated that the effects of LINC00853 on glycolysis and cell proliferation were mediated by PFKFB3. In conclusion, our systemic analyses have highlighted the important roles of cuproptosis-related lncRNAs in PAAD while the prognostic signature based on them showed excellent performance in PAAD patients and is expected to provide clinical guidance for individualized treatment. In addition, our findings provide a novel mechanism by which the LINC00853-PFKFB3 axis critically regulates aerobic glycolysis and cell proliferation in PC cells. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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18 pages, 14032 KiB

Open AccessArticle

High Expression of COA6 Is Related to Unfavorable Prognosis and Enhanced Oxidative Phosphorylation in Lung Adenocarcinoma

by Ming Zhang, Xiaohua Liao, Guanxu Ji, Xianming Fan and Qiang Wu

Int. J. Mol. Sci. 2023, 24(6), 5705; https://doi.org/10.3390/ijms24065705 - 16 Mar 2023

Cited by 7 | Viewed by 2146

Abstract

Mitochondrial metabolism plays an important role in the occurrence and development of cancers. Cytochrome C oxidase assembly factor six (COA6) is essential in mitochondrial metabolism. However, the role of COA6 in lung adenocarcinoma (LUAD) remains unknown. Here we report that the expression of [...] Read more.

Mitochondrial metabolism plays an important role in the occurrence and development of cancers. Cytochrome C oxidase assembly factor six (COA6) is essential in mitochondrial metabolism. However, the role of COA6 in lung adenocarcinoma (LUAD) remains unknown. Here we report that the expression of COA6 mRNA and protein were upregulated in LUAD tissues compared with lung normal tissues. We found that COA6 had high sensitivity and specificity to distinguish LUAD tissues from normal lung tissues shown by a receiver operating characteristic (ROC) curve. In addition, our univariate and multivariate Cox regression analysis indicated that COA6 was an independent unfavorable prognostic factor for LUAD patients. Furthermore, our survival analysis and nomogram showed that a high expression of COA6 mRNA was related to the short overall survival (OS) of LUAD patients. Notably, our weighted correlation network analysis (WGCNA) and functional enrichment analysis revealed that COA6 may participate in the development of LUAD by affecting mitochondrial oxidative phosphorylation (OXPHOS). Importantly, we demonstrated that depletion of COA6 could decrease the mitochondrial membrane potential (MMP), nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH), and adenosine triphosphate (ATP) production in LUAD cells (A549 and H1975), hence inhibiting the proliferation of these cells in vitro. Together, our study strongly suggests that COA6 is significantly associated with the prognosis and OXPHOS in LUAD. Hence, COA6 is highly likely a novel prognostic biomarker and therapeutic target of LUAD. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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14 pages, 2949 KiB

Open AccessArticle

Proteotranscriptomic Discrimination of Tumor and Normal Tissues in Renal Cell Carcinoma

by Áron Bartha, Zsuzsanna Darula, Gyöngyi Munkácsy, Éva Klement, Péter Nyirády and Balázs Győrffy

Int. J. Mol. Sci. 2023, 24(5), 4488; https://doi.org/10.3390/ijms24054488 - 24 Feb 2023

Cited by 1 | Viewed by 2439

Abstract

Clear cell renal carcinoma is the most frequent type of kidney cancer, with an increasing incidence rate worldwide. In this research, we used a proteotranscriptomic approach to differentiate normal and tumor tissues in clear cell renal cell carcinoma (ccRCC). Using transcriptomic data of [...] Read more.

Clear cell renal carcinoma is the most frequent type of kidney cancer, with an increasing incidence rate worldwide. In this research, we used a proteotranscriptomic approach to differentiate normal and tumor tissues in clear cell renal cell carcinoma (ccRCC). Using transcriptomic data of patients with malignant and paired normal tissue samples from gene array cohorts, we identified the top genes over-expressed in ccRCC. We collected surgically resected ccRCC specimens to further investigate the transcriptomic results on the proteome level. The differential protein abundance was evaluated using targeted mass spectrometry (MS). We assembled a database of 558 renal tissue samples from NCBI GEO and used these to uncover the top genes with higher expression in ccRCC. For protein level analysis 162 malignant and normal kidney tissue samples were acquired. The most consistently upregulated genes were IGFBP3, PLIN2, PLOD2, PFKP, VEGFA, and CCND1 (p < 10⁻⁵ for each gene). Mass spectrometry further validated the differential protein abundance of these genes (IGFBP3, p = 7.53 × 10⁻¹⁸; PLIN2, p = 3.9 × 10⁻³⁹; PLOD2, p = 6.51 × 10⁻³⁶; PFKP, p = 1.01 × 10⁻⁴⁷; VEGFA, p = 1.40 × 10⁻²²; CCND1, p = 1.04 × 10⁻²⁴). We also identified those proteins which correlate with overall survival. Finally, a support vector machine-based classification algorithm using the protein-level data was set up. We used transcriptomic and proteomic data to identify a minimal panel of proteins highly specific for clear cell renal carcinoma tissues. The introduced gene panel could be used as a promising tool in the clinical setting. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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20 pages, 7154 KiB

Open AccessArticle

The Prognostic Value and the Oncogenic and Immunological Roles of Vacuolar Protein Sorting Associated Protein 26 A in Pancreatic Adenocarcinoma

by Jihuan Hou, Han Wu, Beibei Xu, Jin Shang, Xuechun Xu, Guixia Li, Haoran Zhang, Wenqing Zhang, Yabin Deng, Xiaoting Hong, Tianhui Hu, Mingqing Zhang and Yanyan Zhan

Int. J. Mol. Sci. 2023, 24(4), 3486; https://doi.org/10.3390/ijms24043486 - 9 Feb 2023

Cited by 2 | Viewed by 2443

Abstract

The identification of the prognostic markers and therapeutic targets might benefit the diagnosis and treatment of pancreatic adenocarcinoma (PAAD), one of the most aggressive malignancies. Vacuolar protein sorting associated protein 26 A (VPS26A) is a candidate prognosis gene for hepatocellular carcinoma, but its [...] Read more.

The identification of the prognostic markers and therapeutic targets might benefit the diagnosis and treatment of pancreatic adenocarcinoma (PAAD), one of the most aggressive malignancies. Vacuolar protein sorting associated protein 26 A (VPS26A) is a candidate prognosis gene for hepatocellular carcinoma, but its expression and function in PAAD remain unknown. The mRNA and protein expression of VPS26A in PAAD was explored and validated by bioinformatics and immunohistochemical analysis. The correlation between VPS26A expression and various clinical parameters, genetic status, diagnostic and prognostic value, survival and immune infiltration were evaluated, and the co-expressed gene-set enrichment analysis for VPS26A was performed. Cytologic and molecular experiments were further carried out to investigate the role and potential mechanism of VPS26A in PAAD. The mRNA and protein levels of VPS26A were elevated in PAAD tissues. High VPS26A expression was associated with the advanced histological type, tumor stage simplified, smoking status and tumor mutational burden score, and the poor prognosis of PAAD patients. VPS26A expression was significantly correlated with immune infiltration and immunotherapy response. VPS26A-co-expressed genes were mainly enriched in the regulation of cell adhesion and actin cytoskeleton and the immune-response-regulating signaling pathway. Our experiments further demonstrated that VPS26A promoted the proliferation, migration and invasion potentials of PAAD cell lines through activating the EGFR/ERK signaling. Our study suggested that VPS26A could be a potential biomarker and a therapeutic target for PAAD through comprehensive regulation of its growth, migration and immune microenvironment. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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19 pages, 7654 KiB

Open AccessArticle

An Angiogenic Gene Signature for Prediction of the Prognosis and Therapeutic Responses of Hepatocellular Carcinoma

by Hongfei Ci, Xufeng Wang, Keyu Shen, Wei Du, Jiaming Zhou, Yan Fu, Qiongzhu Dong and Huliang Jia

Int. J. Mol. Sci. 2023, 24(4), 3324; https://doi.org/10.3390/ijms24043324 - 7 Feb 2023

Cited by 2 | Viewed by 3314

Abstract

Among cancer-related deaths worldwide, hepatocellular carcinoma (HCC) ranks second. The hypervascular feature of most HCC underlines the importance of angiogenesis in therapy. This study aimed to identify the key genes which could characterize the angiogenic molecular features of HCC and further explore therapeutic [...] Read more.

Among cancer-related deaths worldwide, hepatocellular carcinoma (HCC) ranks second. The hypervascular feature of most HCC underlines the importance of angiogenesis in therapy. This study aimed to identify the key genes which could characterize the angiogenic molecular features of HCC and further explore therapeutic targets to improve patients’ prognosis. Public RNAseq and clinical data are from TCGA, ICGC, and GEO. Angiogenesis-associated genes were downloaded from the GeneCards database. Then, we used multi-regression analysis to generate a risk score model. This model was trained on the TCGA cohort (n = 343) and validated on the GEO cohort (n = 242). The predicting therapy in the model was further evaluated by the DEPMAP database. We developed a fourteen-angiogenesis-related gene signature that was distinctly associated with overall survival (OS). Through the nomograms, our signature was proven to possess a better predictive role in HCC prognosis. The patients in higher-risk groups displayed a higher tumor mutation burden (TMB). Interestingly, our model could group subsets of patients with different sensitivities to immune checkpoint inhibitors (ICIs) and Sorafenib. We also predicted that Crizotinib, an anti-angiogenic drug, might be more sensitive to these patients with high-risk scores by the DEPMAP. The inhibitory effect of Crizotinib in human vascular cells was obvious in vitro and in vivo. This work established a novel HCC classification based on the gene expression values of angiogenesis genes. Moreover, we predicted that Crizotinib might be more effective in the high-risk patients in our model. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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17 pages, 7615 KiB

Open AccessArticle

GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation

by Mina Joo, Donghyun Kim, Myung-Won Lee, Hyo Jin Lee and Jin-Man Kim

Int. J. Mol. Sci. 2023, 24(3), 2925; https://doi.org/10.3390/ijms24032925 - 2 Feb 2023

Cited by 12 | Viewed by 3629

Abstract

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer [...] Read more.

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial–mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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19 pages, 11836 KiB

Open AccessArticle

MEK Is a Potential Indirect Target in Subtypes of Head and Neck Cancers

by Bianka Gurbi, Diána Brauswetter, Kinga Pénzes, Attila Varga, Tibor Krenács, Kornél Dános, Ede Birtalan, László Tamás and Miklós Csala

Int. J. Mol. Sci. 2023, 24(3), 2782; https://doi.org/10.3390/ijms24032782 - 1 Feb 2023

Cited by 4 | Viewed by 2040

Abstract

The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is often activated by overexpressed epidermal growth factor receptor (EGFR) and stimulates the progression of HNSCCs. Our research [...] Read more.

The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is often activated by overexpressed epidermal growth factor receptor (EGFR) and stimulates the progression of HNSCCs. Our research was performed on three human papillomavirus (HPV)-negative HNSCC-cell lines: Detroit 562, FaDu and SCC25. Changes in cell viability upon EGFR and/or MEK inhibitors were measured by the MTT method. The protein-expression and phosphorylation profiles of the EGFR-initiated signaling pathways were assessed using Western-blot analysis. The EGFR expression and pY1068-EGFR levels were also studied in the patient-derived HNSCC samples. We found significant differences between the sensitivity of the tumor-cell lines used. The SCC25 line was found to be the most sensitive to the MEK inhibitors, possibly due to the lack of feedback Akt activation through EGFR. By contrast, this feedback activation had an important role in the FaDu cells. The observed insensitivity of the Detroit 562 cells to the MEK inhibitors might have been caused by their PIK3CA mutation. Among HNSCC cell lines, EGFR-initiated signaling pathways are particularly versatile. An ERK/EGFR feedback loop can lead to Akt-pathway activation upon MEK inhibition, and it is related not only to increased amounts of EGFR but also to the elevation of pY1068-EGFR levels. The presence of this mechanism may justify the combined application of EGFR and MEK inhibitors. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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16 pages, 5221 KiB

Open AccessArticle

Carbonic Anhydrase IX Expression and Treatment Response Measured in Rectal Adenocarcinoma Following Neoadjuvant Chemo-Radiotherapy

by Emese Sarolta Bádon, Lívia Beke, Attila Mokánszki, Csilla András and Gábor Méhes

Int. J. Mol. Sci. 2023, 24(3), 2581; https://doi.org/10.3390/ijms24032581 - 30 Jan 2023

Cited by 1 | Viewed by 1817

Abstract

The overexpression of the pH regulator carbonic anhydrase IX (CAIX) due to hypoxic/metabolic stress was reported in various tumors as an adverse prognostic feature. Our retrospective study aimed to investigate the general pattern and dynamics of CAIX expression in rectal adenocarcinoma following preoperative [...] Read more.

The overexpression of the pH regulator carbonic anhydrase IX (CAIX) due to hypoxic/metabolic stress was reported in various tumors as an adverse prognostic feature. Our retrospective study aimed to investigate the general pattern and dynamics of CAIX expression in rectal adenocarcinoma following preoperative neoadjuvant therapy (NAT) in matched initial biopsy and surgical resection samples. A total of 40/55 (72.72%) of the post-treatment samples showed partial CAIX expression, frequently in the proximity of hypoxic tumor areas. CAIX expression showed a significant increase in post-treatment tumors (mean% 21.8 ± 24.9 SD vs. 39.4 ± 29.4 SD, p < 0.0001), that was not obvious in untreated tumors (mean% 15.0 ± 21.3 SD vs. 20 ± 23.02, p = 0.073). CAIXhigh phenotype was associated with mutant KRAS status and lack of pathological regression (WHO Tumor Regression Grade 4 and 5). However, the adverse effect of CAIX on overall or progression-free survival could not be statistically confirmed. In conclusion, the dynamic upregulation of CAIX expression is a general feature of rectal adenocarcinoma following neoadjuvant chemo-radiotherapy indicating therapy-induced metabolic reprogramming and cellular adaptation. A synergism of the CAIX-associated regulatory pathways and the mutant KRAS oncogenic signaling most likely contributes to therapy resistance and survival of residual cancer. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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17 pages, 5535 KiB

Open AccessArticle

RPS24 Is Associated with a Poor Prognosis and Immune Infiltration in Hepatocellular Carcinoma

by Haiyuan Li, Lei Gao, Xiaojuan Kang, Xueyan Wang, Yang Yu, Yaqing Zhang and Hao Chen

Int. J. Mol. Sci. 2023, 24(1), 806; https://doi.org/10.3390/ijms24010806 - 2 Jan 2023

Cited by 9 | Viewed by 3281

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy, with increased mortality and morbidity. Accumulating evidence suggested that 40S ribosomal protein S24 (RPS24) is related to malignant outcomes and progression. However, the role of RPS24 remains unclear in HCC. The [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy, with increased mortality and morbidity. Accumulating evidence suggested that 40S ribosomal protein S24 (RPS24) is related to malignant outcomes and progression. However, the role of RPS24 remains unclear in HCC. The mRNA and protein expression pattern of RPS24 in HCC was explored and confirmed based on the bioinformatics analysis and histological examination. The correlation between RPS24 expression and clinicopathological features, diagnostic value, prognosis, methylation status, and survival were evaluated. Then, we divided the HCC cohort into two groups based on the expression of RPS24, and performed the functional enrichment and immune cells infiltration analysis of RPS24. Furthermore, in vivo and in vitro experiments were performed to investigate the effect of RPS24 on HCC cells. RPS24 was observed to be elevated in HCC samples. RPS24 overexpression or RPS24 promoter methylation contributed to an unfavorable prognosis for HCC patients. The genes in the high RPS24 expression group were mainly enriched in DNA replication, cell cycle E2F targets, and the G2M checkpoint pathway. Moreover, the expression level of RPS24 was significantly related to immune infiltration and immunotherapy response. Our experiments also demonstrated that RPS24 knockdown suppressed the growth of HCC cells and tumor proliferation of the xenograft model. Therefore, RPS24 can be a potential adverse biomarker of HCC prognosis acting through facilitating cell proliferation and the formation of an immunosuppressive microenvironment in HCC. Targeting RPS24 may offer a promising therapeutic option for HCC management. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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Review

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22 pages, 2634 KiB

Open AccessReview

Insights into the Tumor Microenvironment—Components, Functions and Therapeutics

by Kornélia Baghy, Andrea Ladányi, Andrea Reszegi and Ilona Kovalszky

Int. J. Mol. Sci. 2023, 24(24), 17536; https://doi.org/10.3390/ijms242417536 - 15 Dec 2023

Cited by 14 | Viewed by 2168

Abstract

Similarly to our healthy organs, the tumor tissue also constitutes an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and [...] Read more.

Similarly to our healthy organs, the tumor tissue also constitutes an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells and alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix; these processes promote epithelial–mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment; so, the successful inhibition of tumorous matrix remodeling could further enhance the success of antitumor therapy. Over the last decade, significant progress has been made with the introduction of novel immunotherapy that targets the inhibitory mechanisms of T cell activation. However, extensive research is also being conducted on the stromal components and other cell types of the tumor microenvironment (TME) that may serve as potential therapeutic targets. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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23 pages, 1078 KiB

Open AccessReview

The Role of Paxillin Aberrant Expression in Cancer and Its Potential as a Target for Cancer Therapy

by Weixian Liu, Xinxian Huang, Weizhao Luo, Xinguang Liu and Weichun Chen

Int. J. Mol. Sci. 2023, 24(9), 8245; https://doi.org/10.3390/ijms24098245 - 4 May 2023

Cited by 4 | Viewed by 2756

Abstract

Paxillin is a multi-domain adaptor protein. As an important member of focal adhesion (FA) and a participant in regulating cell movement, paxillin plays an important role in physiological processes such as nervous system development, embryonic development, and vascular development. However, increasing evidence suggests [...] Read more.

Paxillin is a multi-domain adaptor protein. As an important member of focal adhesion (FA) and a participant in regulating cell movement, paxillin plays an important role in physiological processes such as nervous system development, embryonic development, and vascular development. However, increasing evidence suggests that paxillin is aberrantly expressed in many cancers. Many scholars have also recognized that the abnormal expression of paxillin is related to the prognosis, metastases, invasion, survival, angiogenesis, and other aspects of malignant tumors, suggesting that paxillin may be a potential cancer therapeutic target. Therefore, the study of how aberrant paxillin expression affects the process of tumorigenesis and metastasis will help to develop more efficacious antitumor drugs. Herein, we review the structure of paxillin and its function and expression in tumors, paying special attention to the multifaceted effects of paxillin on tumors, the mechanism of tumorigenesis and progression, and its potential role in tumor therapy. We also hope to provide a reference for the clinical prognosis and development of new tumor therapeutic targets. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Progression, Prognosis and Therapy)

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