tissue array
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2022 ◽  
Vol 23 (1) ◽  
pp. 535
Author(s):  
Robert J. Rabelo-Fernández ◽  
Ginette S. Santiago-Sánchez ◽  
Rohit K. Sharma ◽  
Abiel Roche-Lima ◽  
Kelvin Carrasquillo Carrion ◽  
...  

Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiao-Wei Zhang ◽  
Lin Li ◽  
Wen-Qian Hu ◽  
Ming-Ning Hu ◽  
Yan Tao ◽  
...  

AbstractDespite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients’ tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yao Wang ◽  
Xiaoyue Xu ◽  
Jacqueline E. Marshall ◽  
Muxue Gong ◽  
Yang Zhao ◽  
...  

Colorectal cancer (CRC) is the third most common diagnosed cancer worldwide, but there are no effective cures for it. Hyaluronan and proteoglycan link protein-1 (HAPLN1) is a component of the extracellular matrix (ECM) proteins and involved in the tumor environment in the colon. Transforming growth factor (TGF)-β is a key cytokine that regulates the deposition of ECM proteins in CRC. However, the role of HAPLN1 in TGF-β contributions to CRC remains unknown. We found that the mRNA expression of HAPLN1 was decreased in tumors from CRC patients compared with healthy controls and normal tissue adjacent to the tumor using two existing microarray datasets. This was validated at the protein level by tissue array from CRC patients (n = 59). HAPLN1 protein levels were also reduced in human CRC epithelial cells after 24 h of TGF-β stimulation, and its protein expression correlated with type I collagen alpha-1 (COL1A1) in CRC. Transfection of HAPLN1 overexpression plasmids into these cells increased protein levels but reduced COL1A1 protein, tumor growth, and cancer cell migration. TGF-β stimulation increased Smad2/3, p-Smad2/3, Smad4, and E-adhesion proteins; however, HAPLN1 overexpression restored these proteins to baseline levels in CRC epithelial cells after TGF-β stimulation. These findings suggest that HAPLN1 regulates the TGF-β signaling pathway to control collagen deposition via the TGF-β signaling pathway and mediates E-adhesion to control tumor growth. Thus, treatments that increase HAPLN1 levels may be a novel therapeutic option for CRC.


2021 ◽  
Author(s):  
Bence Beres ◽  
Maria Yusenko ◽  
Lehel Peterfi ◽  
Gyula Kovacs ◽  
Daniel Banyai

Abstract Purpose Approximately 15% of clinically localised conventional renal cell carcinomas (cRCC) develop metastases within 5 years of follow-up. Sarcomatous cRCC is a highly malignant cancer of the kidney. The aim of our study was to identify biomarkers for estimating the postoperative progression of cRCCs. Methods Global microarray-based gene expression analysis of RCCs with and without sarcomatous changes revealed that a high MMP12 expression was associated with a sarcomatous histology. Additionally, we analysed MMP12 expression using a multi-tissue array comprising 736 cRCC patients without metastasis at the time of surgery. The median follow-up time was 66 ± 29 months. Results Immunohistochemistry revealed MMP12 expression in 187 of 736 cRCCs with good follow-up data. Subsequent Kaplan–Meier analysis revealed that patients with MMP12 positive tumours exhibited a significantly shorter tumour-free survival (p < 0.001). In multivariate Cox regression analysis a weak to strong MMP12 expression indicated a 2.4–2.8 times higher risk of postoperative tumour relapse (p < 0.001; p < 0.003, respectively). Conclusions MMP12 may serve as a biomarker to estimate postoperative cRCC relapse and as a possible target for penfluridol therapy.


2021 ◽  
Author(s):  
Midori Kato-Negishi ◽  
Jun Sawayama ◽  
Masahiro Kawahara ◽  
Shoji Takeuchi

Abstract For the establishment of a reproducible and sensitive assay system for three-dimensional (3D) tissue-based drug screening, it is essential to develop 3D tissue arrays with uniform shapes and high-cell numbers that prevent cell death in the center of the tissue. In recent years, 3D tissue arrays based on spheroids have attracted increased attention. However, they have only been used in specific tissues with hypoxic regions, such as cancer tissues, because nutrient deprivation and hypoxic regions are formed in the core as spheroids grow. Herein we propose a method to array cell-encapsulated tube-like tissue (cell fiber (CF)) with diameters <150 µm to prevent nutrient deprivation and hypoxia using a device that can fix the CFs, section them in uniform sizes and transfer them to a 96-well plate. We fabricated the arrays of CF fragments from cell lines (GT1-7), cancer cells (HeLa), mouse neural stem cells (mNSCs), and differentiated mNSCs, and performed drug response assays. The array of CF fragments assessed drug response differences among different cell types and drug responses specific to 3D tissues. The array of CF fragments may be used as a versatile drug screening system to detect drug sensitivities in various types of tissues.


2021 ◽  
Vol 11 ◽  
Author(s):  
Jill P. Smith ◽  
Hong Cao ◽  
Wenqiang Chen ◽  
Kanwal Mahmood ◽  
Teresa Phillips ◽  
...  

Gastric cancer is a leading cause of cancer-related deaths worldwide. Recently, clinical studies have demonstrated that many of those with advanced gastric cancer are responsive to immune checkpoint antibody therapy, although the median survival even with these new agents is less than 12 months for advanced disease. The gastrointestinal peptide gastrin has been shown to stimulate growth of gastric cancer in a paracrine and autocrine fashion through the cholecystokinin-B receptor (CCK-BR), a receptor that is expressed in at least 56.6% of human gastric cancers. In the current investigation, we studied the role of the gastrin-CCK-BR pathway in vitro and in vivo as well as the expression of the CCK-BR in a human gastric cancer tissue array. CCK-BR and PD-L1 receptor expression and gastrin peptide was found in two murine gastric cancer cells (NCC-S1 and YTN-16) by qRT-PCR and immunocytochemistry. Treatment of NCC-S1 cells with gastrin resulted in increased growth. In vivo, the effects of a cancer vaccine that targets gastrin peptide (polyclonal antibody stimulator—PAS) alone or in combination with a Programed Death-1 antibody (PD-1 Ab) was evaluated in immune competent mice (N = 40) bearing YTN-16 gastric tumors. Mice were treated with PBS, PD-1 Ab (50 µg), PAS (250 µg), or the combination of PD-1 Ab with PAS. Tumor growth was significantly slower than controls in PAS-treated mice, and tumor growth was decreased even more in combination-treated mice. There were no metastases in any of the mice treated with PAS either alone or in combination with PD-1 Ab. Tumor proliferation by the Ki67 staining was significantly decreased in mice treated with PAS monotherapy or the combination therapy. PAS monotherapy or combined with PD-1 Ab increased tumor CD8+ T-lymphocytes and decreased the number of immunosuppressive M2-polarized tumor-associated macrophages. CCK-BR expression was identified in samples from a human tissue array by immunohistochemistry confirming the clinical relevance of this study. These results confirm the significance of the gastrin-CCK-BR signaling pathway in gastric cancer and suggest that the addition of a gastrin vaccine, PAS, to therapy with an immune checkpoint antibody may decrease growth and metastases of gastric cancer by altering the tumor microenvironment.


Bone ◽  
2021 ◽  
Vol 153 ◽  
pp. 116155
Author(s):  
Jiongyu Ren ◽  
Naomi C. Paxton ◽  
Joshua Hammond ◽  
Siamak Saifzadeh ◽  
Roland Steck ◽  
...  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Ting Yen ◽  
May Chien ◽  
Pei-Yi Wu ◽  
Chi-Chang Ho ◽  
Chun-Te Ho ◽  
...  

AbstractMicrosatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.


2021 ◽  
Author(s):  
Ying Wang ◽  
Xiaojuan Pei ◽  
Chunbing Wang ◽  
Zhibo Tan

Abstract Background: Gastric cancer (GC) is still one major reason for cancer-related death worldwide and in China, which ranks the second highest common cancer death rate. It is of great importance to study the molecular mechanisms by which gastric cancer develops. Methods: In this study, in situ hybridization histochemistry (ISHH) was used to examine the lncRNA-GPAND expression levels using gastric cancer tissue array. The real-time live-cell imaging system was used to investigate the effect of GPAND on cell proliferation and apoptosis of GC cell lines. Cell cycle of AGS cell line was examined after GPAND was suppressed using the flow cytometry (FCM). Transwell method was used to study the effect of GPAND on the invasion characteristics of GC cell line. Then the next generation sequencing (NGS) was used to study the potential molecular mechanism and the pathway, and the RT-qPCR was performed to verify the potential targets found by NGS method. Results: It was shown that GPAND was significantly over-expressed in the gastric cancer (GC) tissues (n=215) compared with the paired non-cancerous tissues (n=215), the expression levels of GPAND of GC tissues of TNM stage I-II (n=45) were significantly higher than that of stage III-IV (n=147). It has shown that knockdown of GPAND inhibited the AGS and N87 cell proliferation and promoted the cell apoptosis of AGS and N87 cell lines significantly, and the G1 phase percentage was remarkably increased in GPAND knockdown group of AGS cell line compared with control group. Moreover, suppression of GPAND inhibited the AGS cell invasion significantly. It was found via the NGS method that RUNX2 and MMP13 were significantly up-regulated when the GPAND was over-expressed. Conclusions: These observations suggest the lncRNA-GPAND/RUNX2/MMP13 axis to be a viable therapeutic target for gastric cancer.


Author(s):  
Peng Chen ◽  
Zhiwei He ◽  
Jie Wang ◽  
Jian Xu ◽  
Xueyi Jiang ◽  
...  

p53/p21 signaling plays a vital role in pancreatic cancer (PC) progression. ZWINT was shown to function as an oncoprotein in the progression of multiple cancers. However, the involvement of ZWINT and p53 activation in the progression of PC remains poorly understood. Bioinformatics and tissue array chip analyses were performed to evaluate ZWINT expression in pancreatic cancer. ZWINT mRNA and protein expression were evaluated in normoxia and hypoxia. CHIP was used to evaluate HIF1α interaction with the ZWINT promoter. CCK8, colony formation, EDU, and cell cycle analysis were used to examine PC cell proliferation. Immunoprecipitation and immunofluorescence were used to examine the interaction of ZWINT, MDM2, and p53. p53 activity was evaluated by q-PCR and luciferase assay. Protein degradation and ubiquitination assays were used to analyze the role of ZWINT in p53 ubiquitination. ZWINT was overexpressed in pancreatic cancer and induced in hypoxia. ZWINT promoted pancreatic cancer growth and cell cycle progression. Bioinformatic analysis revealed that ZWINT may regulate the p53 signal pathway. ZWINT interacts with p53 and promotes its ubiquitination and degradation. ZWINT promoted proliferation via p53/p21. Immunohistochemistry of clinical specimens revealed that that ZWINT expression was significantly negatively correlated with p53/p21. Our data showed that hypoxia regulates the expression of ZWINT, which activated p53/p21 signaling pathway to promote PC growth.


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