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Badr N, Elshof LT, Houvast RD, de Muynck LDAN, Crobach ASLP, van Westen GJP, van Vlierberghe RLP, Mieog JSD, Vahrmeijer AL, Kuppen PJK. Evaluation of tumor targets selected from public genomic databases for imaging of pancreatic ductal adenocarcinoma. Sci Rep 2025; 15:17102. [PMID: 40379788 DOI: 10.1038/s41598-025-00517-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 04/29/2025] [Indexed: 05/19/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of approximately 5-7%, and complete surgical resection remains the only curative treatment but is often unfeasible. Fluorescence-guided surgery (FGS) using tumor-targeted probes may improve tumor visualization and facilitate complete resection. This study aimed to identify and validate tumor targets for FGS during PDAC resection procedures. RNA expression data from over 4000 cell surface genes, obtained from public genomic databases, were analyzed to identify genes encoding PDAC-associated proteins. Eleven potential tumor targets were identified, including CEACAM5, TMPRSS4, COL17A1, CLDN18, and AQP5. Protein expression was evaluated by immunohistochemistry (IHC) in tissues from 44 PDAC and 7 chronic pancreatitis (CP) patients. All targets, except COL17A1, showed significantly higher expression in PDAC tissue compared to healthy pancreatic, CP, and duodenal tissue (p < 0.001), as well as in tumor-positive versus tumor-negative lymph nodes. Especially CEACAM5, TMPRSS4, and AQP5 were identified as the most promising targets for distinguishing PDAC from healthy tissues and detecting lymph node metastasis during FGS. The development of probes targeting multiple markers, such as AQP5 with CEACAM5 and/or TMPRSS4, may help overcome interpatient variability and enhance detection across patients.
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Affiliation(s)
- Nada Badr
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
| | - Luca Ten Elshof
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Ruben D Houvast
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | | | - A Stijn L P Crobach
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerard J P van Westen
- Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden, The Netherlands
| | | | - J Sven D Mieog
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
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2
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Tazawa H, Hato S, Yoshino S, Otsuka S, Takeno A, Toyota K, Moriya H, Nozaki I, Tanakaya K, Uchiyama H, Saito A, Kuraoka K, Kato T, Suzuki T, Tashiro H. TMPRSS4 as a prognostic biomarker after gastric cancer surgery in a multicenter retrospective study. Sci Rep 2025; 15:8385. [PMID: 40069485 PMCID: PMC11897406 DOI: 10.1038/s41598-025-93422-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 03/06/2025] [Indexed: 03/15/2025] Open
Abstract
Transmembrane protease serine 4 (TMPRSS4) is a member of the type II transmembrane serine protease family known to be upregulated in many malignancies. We previously showed that TMPRSS4 may be a prognostic biomarker and therapeutic target for gastric cancer (GC), especially in stage III. In this retrospective study conducted at 10 institutions, all 325 patients underwent R0 resection involving D2 lymph node dissection. TMPRSS4 expression was examined using immunohistochemical analysis. TMPRSS4 expression was upregulated in 44.9% of participants. The 5-year overall survival (OS) of the TMPRSS4-positive group was significantly lower than that of the TMPRSS4-negative group (62.4% vs. 76.4%, respectively; p = 0.0149). Univariate analysis revealed that TMPRSS4 upregulation, tumor size, deeper tumor invasion, lymph node metastasis (N), lymphatic invasion, and tumor stage were significant prognostic factors for OS. Multivariate analysis revealed that N and TMPRSS4 upregulation were significant prognostic factors for OS. The 5-year OS rate was examined in two patient groups: the group with the receiver operating characteristic curve cut-off value ≥ 45% for TS-1 (cancer drug formulation) oral dosage and the group with TS-1 dosage cut-off value < 45%. For the patients in the TS-1 dosage ≥ 45% group, there were significant differences in OS between the TMPRSS4-positive and -negative groups (p = 0.0284): the 5-year OS rates of TMPRSS4-positive and -negative groups were 65.2% and 79.2%, respectively. Our findings suggest that TMPRSS4 overexpression is a useful biomarker for GC, and that an anti-TMPRSS4 antibody may have potential as a novel therapeutic agent.
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Affiliation(s)
- Hirofumi Tazawa
- Department of Surgery, NHO Kure Medical Center and Chugoku Cancer Center, 3-1, Aoyama, Kure, Hiroshima, 737-0023, Japan.
| | - Shinji Hato
- Department of Gastroenterological Surgery, NHO National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan
| | - Shigefumi Yoshino
- Department of Surgery, NHO National Hospital Organization Kanmon Medical Center, Shimonoseki, Yamaguchi, Japan
| | - Shinya Otsuka
- Department of Surgery, NHO National Hospital Organization Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Atsusi Takeno
- Department of Surgery, NHO National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Kazuhiro Toyota
- Department of Gastroenterological Surgery, NHO National Hospital Organization Higashihiroshima Medical Center, Higashihiroshima, Japan
| | - Hiromitsu Moriya
- Department of Surgery, NHO National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan
| | - Isao Nozaki
- Department of Surgery, NHO National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Koji Tanakaya
- Department of Surgery, NHO National Hospital Organization Iwakuni Clinical Center, Iwakuni, Yamaguchi, Japan
| | - Hideaki Uchiyama
- Department of Surgery, NHO Fukuokahigashi Medical Center, National Hospital Organization Fukuokahigashi Medical Center, Koga, Fukuoka, Japan
| | - Akihisa Saito
- Department of Diagnostic Pathology, NHO Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Kazuya Kuraoka
- Department of Diagnostic Pathology, NHO Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan
| | - Takeshi Kato
- Department of Surgery, NHO National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Takahisa Suzuki
- Department of Surgery, NHO Kure Medical Center and Chugoku Cancer Center, 3-1, Aoyama, Kure, Hiroshima, 737-0023, Japan
| | - Hirotaka Tashiro
- Department of Surgery, NHO Kure Medical Center and Chugoku Cancer Center, 3-1, Aoyama, Kure, Hiroshima, 737-0023, Japan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biochemical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Qin B, Tang D, Zhang M. miR-149-3p targeting TMPRSS4 regulates the sensitivity to cisplatin to inhibit the progression of lung cancer. BIOMOLECULES & BIOMEDICINE 2024; 25:165-176. [PMID: 39388706 PMCID: PMC11647265 DOI: 10.17305/bb.2024.11163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/24/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024]
Abstract
Lung cancer cells tend to develop resistance to cisplatin (DDP) during continuous chemotherapy, making it crucial to improve DDP sensitivity to enhance therapeutic outcomes. The levels of miR-149-3p in lung tissues and cells, as well as the biological behaviors of lung cancer cells, were analyzed. H446/DDP and A549/DDP cell lines were established to investigate how miR-149-3p affects lung cancer cells' sensitivity to DDP. Bioinformatics analysis predicted transmembrane serine protease 4 (TMPRSS4) as a downstream target of miR-149-3p, which was subsequently confirmed. Western blot analysis was used to examine proteins related to migration, invasion, apoptosis, and TMPRSS4 expression. Additionally, a subcutaneous graft tumor model in nude mice was created to assess the impact of miR-149-3p on tumor growth. In lung cancer tissues and cells, miR-149-3p expression was reduced, while TMPRSS4 expression was elevated. Overexpression of miR-149-3p inhibited cancer progression, promoted apoptosis, and enhanced the chemosensitivity of lung cancer cells to DDP. Moreover, miR-149-3p negatively regulated TMPRSS4, reducing malignancy-associated characteristics of lung cancer cells and further improving their DDP sensitivity. In vivo, high miR-149-3p expression increased the chemosensitivity of cancer cells. In conclusion, miR-149-3p suppresses the aggressive progression of lung cancer by directly downregulating TMPRSS4 and enhances the responsiveness of lung cancer cells to DDP.
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Affiliation(s)
- Beibei Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
- Department of Oncology, LuoYang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan Province, China
| | - Dongfang Tang
- Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Jing’an District, Shanghai, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Wojtukiewicz MZ, Mysliwiec M, Tokajuk A, Kruszewska J, Politynska B, Jamroze A, Wojtukiewicz AM, Tang DG, Honn KV. Tissue factor pathway inhibitor-2 (TFPI-2)-an underappreciated partaker in cancer and metastasis. Cancer Metastasis Rev 2024; 43:1185-1204. [PMID: 39153052 PMCID: PMC11554837 DOI: 10.1007/s10555-024-10205-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/06/2024] [Indexed: 08/19/2024]
Abstract
The coagulation system is known to play an important role in cancer development and metastasis, but the precise mechanisms by which it does so remain incompletely understood. With this in mind, we provide an updated overview of the effects of TFPI-2, a protease inhibitor, on cancer development and metastasis. TFPI-2 interacts with the thrombin cascade and also employs other mechanisms to suppress cancer growth and dissemination, which include extracellular matrix stabilization, promotion of caspase-mediated cell apoptosis, inhibition of angiogenesis and transduction of intracellular signals. Down-regulation of TFPI-2 expression is well documented in numerous types of neoplasms, mainly via promoter methylation. However, the exact role of TFPI-2 in cancer progression and possible approaches to up-regulate TFPI-2 expression warrant further studies. Strategies to reactivate TFPI-2 may represent a promising direction for future anticancer studies and therapy development.
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Affiliation(s)
- Marek Z Wojtukiewicz
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa, 15-027, Bialystok, Poland.
- Department of Clinical Oncology, Comprehensive Cancer Center of Bialystok, 12 Ogrodowa, 15-027, Bialystok, Poland.
| | - Marta Mysliwiec
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa, 15-027, Bialystok, Poland
| | - Anna Tokajuk
- Department of Clinical Oncology, Comprehensive Cancer Center of Bialystok, 12 Ogrodowa, 15-027, Bialystok, Poland
| | - Joanna Kruszewska
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa, 15-027, Bialystok, Poland
| | - Barbara Politynska
- Department of Psychology and Philosophy, Medical University of Bialystok, 37 Szpitalna, 15-295, Bialystok, Poland
- Robinson College, University of Cambridge, Grange Road, Cambridge, CB3 9AN, UK
| | - Anmbreen Jamroze
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Anna M Wojtukiewicz
- Department of Psychology and Philosophy, Medical University of Bialystok, 37 Szpitalna, 15-295, Bialystok, Poland
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Kenneth V Honn
- Department of Pathology-School of Medicine, Bioactive Lipids Research Program, Wayne State University, 540 East Canfield Avenue, Detroit, MI, 48201, USA
- Karmanos Cancer Institute, 4100 John R St, Detroit, MI, 48201, USA
- Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI, 48202, USA
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5
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Tazuma S, Sudo T, Ishikawa A, Yamaguchi A, Shibata Y, Ishida Y, Kuraoka K, Uemura K, Takahashi S, Tashiro H. Effects of transmembrane serine protease 4 on the survival in patients with pancreatic ductal adenocarcinoma undergoing surgery followed by adjuvant chemotherapy. Surg Today 2024; 54:1208-1219. [PMID: 38637344 DOI: 10.1007/s00595-024-02824-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/25/2024] [Indexed: 04/20/2024]
Abstract
PURPOSE The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery. METHODS The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil. RESULTS The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells. CONCLUSIONS TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Sho Tazuma
- Department of Surgery, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Takeshi Sudo
- Department of Surgery, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Akira Ishikawa
- Department of Diagnostic Pathology, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Atsushi Yamaguchi
- Department of Gastroenterology, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Yoshiyuki Shibata
- Department of Surgery, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Yuko Ishida
- Institute for Clinical Laboratory, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Aoyama, Kure, Hiroshima, 737-0023, Japan
| | - Kazuya Kuraoka
- Department of Diagnostic Pathology, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan
| | - Kenichiro Uemura
- Department of Surgery, Graduate School of Biochemical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Shinya Takahashi
- Department of Surgery, Graduate School of Biochemical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Hirotaka Tashiro
- Department of Surgery, Kure Medical Center/Chugoku Cancer Center, National Hospital Organization, 3-1, Kure, Hiroshima, 737-0023, Japan.
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Shibata Y, Sudo T, Tazuma S, Tanimine N, Onoe T, Shimizu Y, Yamaguchi A, Kuraoka K, Takahashi S, Tashiro H. Transmembrane serine protease 4 expression in the prognosis of radical resection for biliary tract cancer. World J Gastrointest Surg 2024; 16:2555-2564. [PMID: 39220090 PMCID: PMC11362932 DOI: 10.4240/wjgs.v16.i8.2555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/23/2024] [Accepted: 06/25/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Recent advancements in biliary tract cancer (BTC) treatment have expanded beyond surgery to include adjuvant therapy, yet the prognosis remains poor. Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC. AIM To determine transmembrane serine protease 4 (TMPRSS4) utility as a prognostic biomarker of radical resection for BTC. METHODS Medical records of patients who underwent radical resection for BTC, excluding intrahepatic cholangiocarcinoma, were retrospectively reviewed. The associations between TMPRSS4 expression and clinicopathological factors, overall survival, and recurrence-free survival were analyzed. RESULTS Among the 85 patients undergoing radical resection for BTC, 46 (54%) were TMPRSS4-positive. The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9 (CA19-9) values and greater lymphatic invasion than the TMPRSS4-negative group (P = 0.019 and 0.039, respectively). Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group (median survival time: 25.3 months vs not reached, P < 0.001; median survival time: 28.7 months vs not reached, P = 0.043, respectively). Multivariate overall survival analysis indicated TMPRSS4 positivity, pT3/T4, and resection status R1 were independently associated with poor prognosis (P = 0.032, 0.035 and 0.030, respectively). TMPRSS4 positivity correlated with preoperative CA19-9 values ≥ 37 U/mL and pathological tumor size ≥ 30 mm (P = 0.016 and 0.038, respectively). CONCLUSION TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.
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Affiliation(s)
- Yoshiyuki Shibata
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Takeshi Sudo
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Sho Tazuma
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Naoki Tanimine
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Takashi Onoe
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Yosuke Shimizu
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Atsushi Yamaguchi
- Department of Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Kazuya Kuraoka
- Department of Diagnostic Pathology, National Hospital Organization Kure Medical Center, and Chugoku Cancer Center, Hiroshima 737-0023, Japan
| | - Shinya Takahashi
- Department of Surgery, Graduate School of Biochemical and Health Science, Hiroshima University, Hiroshima 734-8551, Japan
| | - Hirotaka Tashiro
- Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
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Dai YW, Pan YT, Lin DF, Chen XH, Zhou X, Wang WM. Bulk anda single-cell transcriptome profiling reveals the molecular characteristics of T cell-mediated tumor killing in pancreatic cancer. Heliyon 2024; 10:e27216. [PMID: 38449660 PMCID: PMC10915414 DOI: 10.1016/j.heliyon.2024.e27216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/08/2024] Open
Abstract
Background Despite the potential of immune checkpoint blockade (ICB) as a promising treatment for Pancreatic adenocarcinoma (PAAD), there is still a need to identify specific subgroups of PAAD patients who may benefit more from ICB. T cell-mediated tumor killing (TTK) is the primary concept behind ICB. We explored subtypes according to genes correlated with the sensitivity to TKK and unraveled their underlying associations for PAAD immunotherapies. Methods Genes that control the responsiveness of T cell-induced tumor destruction (GSTTK) were examined in PAAD, focusing on their varying expression levels and association with survival results. Moreover, samples with PAAD were separated into two subsets using unsupervised clustering based on GSTTK. Variability was evident in the tumor immune microenvironment, genetic mutation, and response to immunotherapy among different groups. In the end, we developed TRGscore, an innovative scoring system, and investigated its clinical and predictive significance in determining sensitivity to immunotherapy. Results Patients with PAAD were categorized into 2 clusters based on the expression of 52 GSTTKs, which showed varying levels and prognostic relevance, revealing unique TTK patterns. Survival outcome, immune cell infiltration, immunotherapy responses, and functional enrichment are also distinguished among the two clusters. Moreover, we found the CATSPER1 gene promotes the progression of PAAD through experiments. In addition, the TRGscore effectively predicted the responses to chemotherapeutics or immunotherapy in patients with PAAD and overall survival. Conclusions TTK exerted a vital influence on the tumor immune environment in PAAD. A greater understanding of TIME characteristics was gained through the evaluation of the variations in TTK modes across different tumor types. It highlights variations in the performance of T cells in PAAD and provides direction for improved treatment approaches.
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Affiliation(s)
- Yin-wei Dai
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ya-ting Pan
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dan-feng Lin
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-hu Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiang Zhou
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei-ming Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Sari B, Gulbey O, Hamill KJ. Laminin 332 expression levels predict clinical outcomes and chemotherapy response in patients with pancreatic adenocarcinoma. Front Cell Dev Biol 2023; 11:1242706. [PMID: 37779898 PMCID: PMC10540629 DOI: 10.3389/fcell.2023.1242706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 08/30/2023] [Indexed: 10/03/2023] Open
Abstract
Poor outcomes and chemotherapy resistance for patients with pancreatic adenocarcinoma (PAAD) are a challenge worldwide, and new or improved prognostic biomarkers are urgently required. Individual laminin family members have been established as cancer-associated markers, predicting patient outcomes in many cancer types, including PAAD. Here, we used multiple modalities including RNAseq and gene chip, and genomic and proteomic data to examine the relationships of all laminin genes in PAAD with clinical outcomes. These analyses identified that LAMA3, LAMB3, and LAMC2 expression levels are increased at the mRNA and protein levels in PAAD tumours with evidence of co-regulation. Increased expression of all three genes was associated with decreased promoter methylation status, TP53 mutations, and altered receptor tyrosine kinase (RTK) pathways. Clinically, high LAMA3, LAMB3, and LAMC2 transcript abundance was each related to an advanced histological grade. Moreover, high expression of these genes individually predicted poor patient survival, while a signature of combined high expression of LAMA3, LAMB3, and LAMC2 was a stronger predictor of patient outcomes than each gene alone. Interestingly, cell lines with high expression of LM332 chains were not sensitive to the commonly used PAAD chemotherapy drugs paclitaxel and gemcitabine; however, increased sensitivity was evident for erlotinib, afatinib, gefitinib, and cetuximab epidermal growth factor (EGFR) RTK inhibitors. To explore possible mechanisms, we investigated co-expressed genes, identifying eight hub genes, namely, GJB3, ITGB6, SERPINB5, GPRC5A, PLEK2, TMPRSS4, P2RY2, and TRIM29, which are co-expressed with all three of LAMA3, LAMB3, and LAMC2. Of these, only SERPINB5 provided a stronger predictive value than the laminin-encoding genes. Together, these multiple integrated analyses suggest that the combined expression of LM332 is a useful prognostic biomarker for PAAD and could help patient stratification and therapeutic selection.
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Affiliation(s)
- Bilge Sari
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Ozcan Gulbey
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Kevin J. Hamill
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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9
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Kircali MF, Turanli B. Idiopathic Pulmonary Fibrosis Molecular Substrates Revealed by Competing Endogenous RNA Regulatory Networks. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:381-392. [PMID: 37540140 DOI: 10.1089/omi.2023.0072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic disease of the lung with poor prognosis. Fibrosis results from remodeling of the interstitial tissue. A wide range of gene expression changes are observed, but the role of micro RNAs (miRNAs) and circular RNAs (circRNA) is still unclear. Therefore, this study aimed to establish an messenger RNA (mRNA)-miRNA-circRNA competing endogenous RNA (ceRNA) regulatory network to uncover novel molecular signatures using systems biology tools. Six datasets were used to determine differentially expressed genes (DEGs) and miRNAs (DEmiRNA). Accordingly, protein-protein, mRNA-miRNA, and miRNA-circRNA interactions were constructed. Modules were determined and further analyzed in the Drug Gene Budger platform to identify potential therapeutic compounds. We uncovered common 724 DEGs and 278 DEmiRNAs. In the protein-protein interaction network, TMPRSS4, ESR2, TP73, CLEC4E, and TP63 were identified as hub protein coding genes. The mRNA-miRNA interaction network revealed two modules composed of ADRA1A, ADRA1B, hsa-miR-484 and CDH2, TMPRSS4, and hsa-miR-543. The DEmiRNAs in the modules further analyzed to propose potential circRNA regulators in the ceRNA network. These results help deepen the understanding of the mechanisms of IPF. In addition, the molecular leads reported herein might inform future innovations in diagnostics and therapeutics research and development for IPF.
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Affiliation(s)
- Muhammed Fatih Kircali
- School of Medicine, Marmara University, Istanbul, Türkiye
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Türkiye
| | - Beste Turanli
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Türkiye
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10
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Kim S. TMPRSS4, a type II transmembrane serine protease, as a potential therapeutic target in cancer. Exp Mol Med 2023; 55:716-724. [PMID: 37009799 PMCID: PMC10167312 DOI: 10.1038/s12276-023-00975-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/12/2023] [Accepted: 01/24/2023] [Indexed: 04/04/2023] Open
Abstract
Proteases are involved in almost all biological processes, implying their importance for both health and pathological conditions. Dysregulation of proteases is a key event in cancer. Initially, research identified their role in invasion and metastasis, but more recent studies have shown that proteases are involved in all stages of cancer development and progression, both directly through proteolytic activity and indirectly via regulation of cellular signaling and functions. Over the past two decades, a novel subfamily of serine proteases called type II transmembrane serine proteases (TTSPs) has been identified. Many TTSPs are overexpressed by a variety of tumors and are potential novel markers of tumor development and progression; these TTSPs are possible molecular targets for anticancer therapeutics. The transmembrane protease serine 4 (TMPRSS4), a member of the TTSP family, is upregulated in pancreatic, colorectal, gastric, lung, thyroid, prostate, and several other cancers; indeed, elevated expression of TMPRSS4 often correlates with poor prognosis. Based on its broad expression profile in cancer, TMPRSS4 has been the focus of attention in anticancer research. This review summarizes up-to-date information regarding the expression, regulation, and clinical relevance of TMPRSS4, as well as its role in pathological contexts, particularly in cancer. It also provides a general overview of epithelial-mesenchymal transition and TTSPs.
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Affiliation(s)
- Semi Kim
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Korea.
- Department of Functional Genomics, Korea University of Science and Technology, Daejon, 34113, Korea.
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Mei Y, Liang D, Ai B, Wang T, Guo S, Jin G, Yu D. Genome-wide identification of A-to-I RNA editing events provides the functional implications in PDAC. Front Oncol 2023; 13:1092046. [PMID: 36895481 PMCID: PMC9990869 DOI: 10.3389/fonc.2023.1092046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/26/2023] [Indexed: 02/23/2023] Open
Abstract
Introduction RNA editing, a wide-acknowledged post-transcriptional mechanism, has been reported to be involved in the occurrence and development of cancer, especially the abnormal alteration of adenosine to inosine. However, fewer studies focus on pancreaticcancer. Therefore, we aimed to explore the possible linkages between altered RNA editing events and the development of PDAC. Method We characterized the global A-to-I RNA editing spectrum from RNA and matched whole-genome sequencing data of 41 primary PDAC and adjacent normal tissues. The following analyses were performed: different editing level and RNA expression analysis,pathway analysis, motif analysis, RNA secondary structure analysis, alternative splicing events analysis, and survival analysis.The RNA editing of single-cell RNA public sequencing data was also characterized. Result A large number of adaptive RNA editing events with significant differences in editing levels were identified, which are mainly regulated by ADAR1. Moreover, RNA editing in tumors has a higher editing level and more abundant editing sites in general. 140genes were screened out since they were identified with significantly different RNA editing events and were significantly different in expression level between tumor and matched normal samples. Further analysis showed a preference that in the tumor-specific group, they are mainly enriched in cancer-related signal pathways, while in the normal tissue-specific group, they are mainly enriched in pancreatic secretion. At the same time, we also found positively selected differentially edited sites in a series of cancer immune genes, including EGF, IGF1R, and PIK3CD. RNA editing might participate in pathogenisis of PDAC through regulating the alternative splicing and RNA secondary structure of important genesto further regulate gene expression and protein synthesis, including RAB27B and CERS4. Furthermore, single cell sequencing results showed that type2 ductal cells contributed the most to RNA editing events in tumors. Conclusion RNA editing is an epigenetic mechanism involved in the occurrence and development of pancreatic cancer, which has the potential to diagnose of PDAC and is closely related to the prognosis.
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Affiliation(s)
- Yue Mei
- Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.,Shanghai Key Laboratory of Cell Engineering, Shanghai, China
| | - Dong Liang
- Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.,Shanghai Key Laboratory of Cell Engineering, Shanghai, China
| | - Bin Ai
- Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.,Shanghai Key Laboratory of Cell Engineering, Shanghai, China
| | - Tengjiao Wang
- Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.,Shanghai Key Laboratory of Cell Engineering, Shanghai, China
| | - Shiwei Guo
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Gang Jin
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Dong Yu
- Department of Precision Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, China.,Shanghai Key Laboratory of Cell Engineering, Shanghai, China
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Sha J, Song J, Huang Y, Zhang Y, Wang H, Zhang Y, Suo H. Inhibitory Effect and Potential Mechanism of Lactobacillus plantarum YE4 against Dipeptidyl Peptidase-4. Foods 2021; 11:foods11010080. [PMID: 35010205 PMCID: PMC8750294 DOI: 10.3390/foods11010080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 12/25/2021] [Indexed: 12/23/2022] Open
Abstract
This study investigated the inhibitory effect and mechanism of 12 LAB strains isolated from Chinese fermented foods on dipeptidyl peptidase-4 (DPP-4) using the Caco-2 cell model. The results showed that the inhibitory effect of cell-free extracts (CFEs) collected from each LAB strain on DPP-4 was higher than that of the cell-free excretory supernatants. The CFEs from Lactobacillus plantarum YE4 (YE4-CFE) exhibited the strongest DPP-4 inhibitory activity (24.33% inhibition). Furthermore, YE4-CFE altered the TNF and MAPK signaling pathways. Additionally, the YE4-CFE ultrafiltration fraction (<3 kDa) displayed a similar DPP-4 inhibitory activity to YE4-CFE. UHPLC-MS/MS identified 19 compounds with a relative proportion of more than 1% in the <3 kDa fraction, and adenine, acetylcholine, and L-phenylalanine were the top three substances in terms of proportion. Altogether, the inhibitory effect of YE4-CFE on DPP-4 was associated with the TNF and MAPK signaling pathways, and with the high proportion of adenine, acetylcholine, and L-phenylalanine.
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Affiliation(s)
- Jia Sha
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Yechuan Huang
- College of Bioengineering, Jingchu University of Technology, Jingmen 448000, China
| | - Yuhong Zhang
- Institute of Food Sciences and Technology, Tibet Academy of Agricultural and Animal Husbandry Sciences, Lhasa 850000, China
| | - Hongwei Wang
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Yu Zhang
- College of Food Science, Southwest University, Chongqing 400715, China
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing 400715, China
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Cheng Y, Wang G, Zhao L, Dai S, Han J, Hu X, Zhou C, Wang F, Ma H, Li B, Meng Z. Periplocymarin Induced Colorectal Cancer Cells Apoptosis Via Impairing PI3K/AKT Pathway. Front Oncol 2021; 11:753598. [PMID: 34900704 PMCID: PMC8655334 DOI: 10.3389/fonc.2021.753598] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/04/2021] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, and approximately one-third of CRC patients present with metastatic disease. Periplocymarin (PPM), a cardiac glycoside isolated from Periploca sepium, is a latent anticancer compound. The purpose of this study was to explore the effect of PPM on CRC cells. CRC cells were treated with PPM and cell viability was evaluated by CCK-8 assay. Flow cytometry and TUNEL staining were performed to assess cell cycle and apoptosis. Quantitative proteomics has been used to check the proteins differentially expressed by using tandem mass tag (TMT) labeling and liquid chromatography–tandem mass spectrometry. Bioinformatic analysis was undertaken to identify the biological processes that these differentially expressed proteins are involved in. Gene expression was analyzed by western blotting. The effect of PPM in vivo was primarily checked in a subcutaneous xenograft mouse model of CRC, and the gene expression of tumor was checked by histochemistry staining. PPM could inhibit the proliferation of CRC cells in a dose-dependent manner, induce cell apoptosis and promote G0/G1 cell cycle arrest. A total of 539 proteins were identified differentially expressed following PPM treatment, where among those there were 286 genes upregulated and 293 downregulated. PPM treatment caused a pro-apoptosis gene expression profile both in vivo and in vitro, and impaired PI3K/AKT signaling pathway might be involved. In addition, PPM treatment caused less detrimental effects on blood cell, hepatic and renal function in mice, and the anti-cancer effect was found exaggerated by PPM+5-FU combination treatment. PPM may perform anti-CRC effects by promoting cell apoptosis and this might be achieved by targeting PI3K/AKT pathway. PPM might be a safe and promising anti-cancer drug that needs to be further studied.
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Affiliation(s)
- Yi Cheng
- Department of Dermatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiying Wang
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Gastrointestinal Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lianmei Zhao
- Scientific Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Suli Dai
- Scientific Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jing Han
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xuhua Hu
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Feifei Wang
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongqing Ma
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baokun Li
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zesong Meng
- Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Hakobyan S, Loeffler-Wirth H, Arakelyan A, Binder H, Kunz M. A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy. Int J Mol Sci 2021; 22:ijms22137165. [PMID: 34281234 PMCID: PMC8268681 DOI: 10.3390/ijms22137165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/22/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (n = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (RAB6B), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (MSR1), Collagen Type XI Alpha 2 Chain (COLL11A2), and LY6/PLAUR Domain Containing 1 (LYPD1). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (CHEK1) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (SF3A3, SF3B3), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.
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Affiliation(s)
- Siras Hakobyan
- Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia; (S.H.); (A.A.)
| | - Henry Loeffler-Wirth
- Interdisciplinary Centre for Bioinformatics, University of Leipzig, Härtelstr. 16–18, 04107 Leipzig, Germany; (H.L.-W.); (H.B.)
| | - Arsen Arakelyan
- Institute of Molecular Biology NAS RA, Yerevan 0014, Armenia; (S.H.); (A.A.)
| | - Hans Binder
- Interdisciplinary Centre for Bioinformatics, University of Leipzig, Härtelstr. 16–18, 04107 Leipzig, Germany; (H.L.-W.); (H.B.)
| | - Manfred Kunz
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Philipp-Rosenthal-Str. 23, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-341-9718610; Fax: +49-341-9718609
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