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Kopec K, Quaranto D, DeSouza NR, Jarboe T, Islam HK, Moscatello A, Li XM, Geliebter J, Tiwari RK. The HOX Gene Family's Role as Prognostic and Diagnostic Biomarkers in Hematological and Solid Tumors. Cancers (Basel) 2025; 17:262. [PMID: 39858044 PMCID: PMC11763641 DOI: 10.3390/cancers17020262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
The HOX gene family encodes for regulatory transcription factors that play a crucial role in embryogenesis and differentiation of adult cells. This highly conserved family of genes consists of thirty-nine genes in humans that are located in four clusters, A-D, on different chromosomes. While early studies on the HOX gene family have been focused on embryonic development and its related disorders, research has shifted to examine aberrant expression of HOX genes and the subsequent implication in cancer prediction and progression. Due to their role of encoding master regulatory transcription factors, the abnormal expression of HOX genes has been shown to affect all stages of tumorigenesis and metastasis. This review highlights the novel role of the HOX family's clinical relevance as both prognostic and diagnostic biomarkers in hematological and solid tumors.
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Affiliation(s)
- Kaci Kopec
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Danielle Quaranto
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Nicole R. DeSouza
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Tara Jarboe
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Humayun K. Islam
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Augustine Moscatello
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Xiu-Min Li
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
- Department of Dermatology, New York Medical College, Valhalla, NY 10595, USA
| | - Jan Geliebter
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Raj K. Tiwari
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
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Zhang HM, Wang GH, Sun SW, Yuan L. Advancing prognostic precision in gastric cancer with an immunoinflammatory index. World J Gastroenterol 2024; 30:4754-4758. [PMID: 39610779 PMCID: PMC11580602 DOI: 10.3748/wjg.v30.i44.4754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/12/2024] [Accepted: 10/23/2024] [Indexed: 11/12/2024] Open
Abstract
Gastric cancer remains a major global health challenge with high morbidity and mortality rates. Recent advancements in immunology and inflammation research have highlighted the crucial roles that these biological processes play in tumor progression and patient outcomes. This has sparked new interest in developing prognostic biomarkers that integrate these two key biological processes. In this letter, we discuss the recent study by Ba et al, which proposed a novel prognostic immunoinflammatory index for patients with gastric cancer. We underscore the importance of this research, its potential impact on medical practice, and the prospective avenues for further investigation in this rapidly emerging area of study.
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Affiliation(s)
- Hong-Mei Zhang
- College of Life Science, Northeast Forestry University, Harbin 150040, Heilongjiang Province, China
| | - Guo-Hua Wang
- College of Computer and Control Engineering, Northeast Forestry University, Harbin 150040, Heilongjiang Province, China
| | - Shan-Wen Sun
- College of Life Science, Northeast Forestry University, Harbin 150040, Heilongjiang Province, China
| | - Lei Yuan
- Department of Hepatobiliary Surgery, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
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Zhang Y, Li J. Recent advancements in understanding of biological role of homeobox C9 in human cancers. World J Clin Oncol 2024; 15:1168-1176. [PMID: 39351453 PMCID: PMC11438841 DOI: 10.5306/wjco.v15.i9.1168] [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: 05/16/2024] [Revised: 07/14/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024] Open
Abstract
Homeobox (HOX) C9, a member of the HOX family, is an important transcription factor, and it plays a significant role in various biological processes. This family of genes is highly valued for their essential roles in establishing and maintaining the body axis during embryonic development and adult tissues. Further, HOXC9 plays a central role in neuronal differentiation, angiogenesis, and adipose distribution, which are essential for the development of the nervous system, maturation of tissues and organs, and maintenance of energy balance and metabolic health. Recent research has found that abnormal HOXC9 expression is closely associated with the development and progression of various tumor types. The HOXC9 expression level can be an indicator of tumor prognosis. Therefore, elucidating the association between HOXC9 expression and its regulatory mechanisms and tumorigenesis can provide novel insights on the diagnosis and treatment of patients with cancer.
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Affiliation(s)
- Yong Zhang
- Department of Clinical Laboratory, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
| | - Jing Li
- Department of Respiratory and Critical Care Medicine, The Affiliated Lianyungang Oriental Hospital of Kangda College of Nanjing Medical University, Lianyungang 222042, Jiangsu Province, China
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Liu L, Zhang Z, Jiang C, Zhu Y, Han R, Wu L, Xu Y. HOXC9 characterizes a suppressive tumor immune microenvironment and integration with multiple immune biomarkers predicts response to PD-1 blockade plus chemotherapy in lung adenocarcinoma. Aging (Albany NY) 2024; 16:4841-4861. [PMID: 38446596 PMCID: PMC10968688 DOI: 10.18632/aging.205637] [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: 09/28/2023] [Accepted: 02/13/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND The quest for dependable biomarkers to predict responses to immune checkpoint inhibitors (ICIs) combined with chemotherapy in advanced non-small cell lung cancer remains unfulfilled. HOXC9, known for its role in oncogenesis and creating a suppressive tumor microenvironment (TME), shows promise in enhancing predictive precision when included as a TME biomarker. This study explores the predictive significance of HOXC9 for ICI plus chemotherapy efficacy in lung adenocarcinoma (LUAD). METHODS Following the bioinformatic findings, assays were performed to ascertain the effects of Hoxc9 on oncogenesis and response to programmed death 1 (PD-1) blockade. Furthermore, a cohort of LUAD patients were prospectively enrolled to receive anti-PD-1 plus chemotherapy. Based on the expression levels, baseline characteristics, and clinical outcomes, the predictive potential of HOXC9, PD-L1, CD4, CD8, CD68, and FOXP3 was integrally analyzed. HOXC9 not only mediated oncogenesis, but also corelated with suppressive TME. CMT167 and LLC cell lines unveiled the impacts of Hoxc9 on proliferation, invasion, and migration. Subsequently, tumor-bearing murine models were established to validate the inverse relationship between Hoxc9 expression and effective CD8+ T cells. RESULTS Inhibition of Hoxc9 significantly curtailed tumor growth (P<0.05), independent of PD-1 blockade. In patient studies, while individual markers fell short in prognosticating survival, a notable elevation in CD8-positive expression was observed in responders (P=0.042). Yet, the amalgamation of HOXC9 with other markers provided a more distinct differentiation between responders and non-responders. Notably, patients displaying PD-L1+/HOXC9- and CD8+/HOXC9- phenotypes exhibited significantly prolonged progression-free survival. CONCLUSIONS The expression of HOXC9 may serve as a biomarker to amplifying predictive efficacy for ICIs plus chemotherapy, which is also a viable oncogene and therapeutic target for immunotherapy in LUAD.
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Affiliation(s)
- Liang Liu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Zhenshan Zhang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201315, China
| | - Chenxue Jiang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Yaoyao Zhu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Ruiqin Han
- State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100191, China
| | - Leilei Wu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Yaping Xu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
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Sun QH, Kuang ZY, Zhu GH, Ni BY, Li J. Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers. World J Gastrointest Oncol 2024; 16:300-313. [PMID: 38425402 PMCID: PMC10900144 DOI: 10.4251/wjgo.v16.i2.300] [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: 10/14/2023] [Revised: 12/31/2023] [Accepted: 01/19/2024] [Indexed: 02/02/2024] Open
Abstract
MicroRNAs (miRNAs) have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells (CSCs). The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells (GCSCs). Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs. This review summarizes the coding process and biological functions of miRNAs and demonstrates their role and efficacy in gastric cancer (GC) metastasis, drug resistance, and apoptosis, especially in the regulatory mechanism of GCSCs. It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis, apart from the initial formation of GC. It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC. We believe that this review may help in designing novel therapeutic approaches for GC.
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Affiliation(s)
- Qian-Hui Sun
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Zi-Yu Kuang
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Guang-Hui Zhu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Bao-Yi Ni
- Department of Oncology, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Jie Li
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Yang F, Wu Y, Hockey R, Doust J, Mishra GD, Montgomery GW, Mortlock S. Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management. Cell Rep Med 2023; 4:101250. [PMID: 37909040 PMCID: PMC10694629 DOI: 10.1016/j.xcrm.2023.101250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/26/2023] [Accepted: 09/27/2023] [Indexed: 11/02/2023]
Abstract
In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed. Using large-scale datasets, we report a genetic correlation between endometriosis and irritable bowel syndrome (IBS), peptic ulcer disease (PUD), gastro-esophageal reflux disease (GORD), and a combined GORD/PUD medicated (GPM) phenotype. Mendelian randomization analyses support a causal relationship between genetic predisposition to endometriosis and IBS and GPM. Identification of shared risk loci highlights biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, and potential therapeutic drug targets (CCKBR; PDE4B). Higher use of IBS, GORD, and PUD medications in women with endometriosis and higher use of hormone therapies in women with IBS, GORD, and PUD, support the co-occurrence of these conditions and highlight the potential for drug repositioning and drug contraindications. Our results provide evidence of shared disease etiology and have important clinical implications for diagnostic and treatment decisions for both diseases.
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Affiliation(s)
- Fei Yang
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Yeda Wu
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Richard Hockey
- The University of Queensland, NHMRC Centre for Research Excellence on Women and Non-communicable Diseases (CREWaND), School of Public Health, Herston Road, Herston, QLD, Australia
| | - Jenny Doust
- The University of Queensland, NHMRC Centre for Research Excellence on Women and Non-communicable Diseases (CREWaND), School of Public Health, Herston Road, Herston, QLD, Australia
| | - Gita D Mishra
- The University of Queensland, NHMRC Centre for Research Excellence on Women and Non-communicable Diseases (CREWaND), School of Public Health, Herston Road, Herston, QLD, Australia
| | - Grant W Montgomery
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Sally Mortlock
- The Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
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Li Z, Zhang C, Zhang Q, Dong Y, Sha X, Jiang M, Yan J, Wang W, Li H, Zhang Y, Zhou YL. Identification of a potential bioinformatics-based biomarker in keloids and its correlation with immune infiltration. Eur J Med Res 2023; 28:476. [PMID: 37915086 PMCID: PMC10621210 DOI: 10.1186/s40001-023-01421-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 10/01/2023] [Indexed: 11/03/2023] Open
Abstract
Keloid formation is a pathological consequence resulting from cutaneous irritation and injury, primarily attributed to excessive collagen matrix deposition and fibrous tissue proliferation. Chronic inflammation, left uncontrolled over an extended period, also stands as a substantial contributing factor. The precise mechanisms underlying keloid formation remain unclear. Therefore, this study aimed to identify key genes for diagnostic purposes. To achieve this, we used two Gene Expression Omnibus (GEO) data sets to identify differentially expressed genes. We identified one particular gene, homeobox C9 (HOXC9), using a thorough strategy involving two algorithms (least absolute shrinkage and selection operator and support vector machine-recursive feature elimination) and weighted gene co-expression network analysis. We then assessed its expression in normal and keloid tissues. In addition, we explored its temporal expression patterns via Mfuzz time clustering analysis. In our comprehensive analysis, we observed that immune infiltration, as well as cell proliferation, are crucial to keloid formation. Thus, we investigated immune cell infiltration in the keloid and normal groups, as well as the correlation between HOXC9 and these immune cells. It was found that HOXC9 was closely associated with the immune microenvironment of keloids. This shows that HOXC9 can serve as a potential biomarker and therapeutic target for keloids.
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Affiliation(s)
- Zihan Li
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
- The Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Chuwei Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Qingrong Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Institute of Burn Research, Southwest Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yipeng Dong
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Xinyu Sha
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Jiang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Jun Yan
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Nantong University, Nantong, China
| | - Wenmiao Wang
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Houqiang Li
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yi Zhang
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China.
| | - You Lang Zhou
- Department of Burn and Plastic Surgery, Affiliated Hospital of Nantong University, Nantong, China.
- The Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong, China.
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Gao L, Rong H. Potential mechanisms and prognostic model of eRNAs-regulated genes in stomach adenocarcinoma. Sci Rep 2022; 12:16545. [PMID: 36192427 PMCID: PMC9529949 DOI: 10.1038/s41598-022-20824-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/19/2022] [Indexed: 11/09/2022] Open
Abstract
Gastric Carcinoma is the fourth leading cause of cancer deaths worldwide, in which stomach adenocarcinoma (STAD) is the most common histological type. A growing amount of evidence has suggested the importance of enhancer RNAs (eRNAs) in the cancer. However, the potential mechanism of eRNAs in STAD remains unclear. The eRNAs-regulated genes (eRRGs) were identified through four different enhancer resources. The differentially expressed eRRGs were obtained by ‘DESeq2’ R package. The prognosis prediction model was constructed by Cox and Lasso regression analysis. The ‘ChAMP’ R package and ‘maftools’ R package were used to investigate the multi-omics characters. In this study, combining the concept of contact domain, a total of 9014 eRRGs including 4926 PCGs and 4088 lncRNAs were identified and these eRRGs showed higher and more stable expression. Besides, the functions of these genes were mainly associated with tumor-related biological processes. Then, a prognostic prediction model was constructed and the AUC values of the 1-, 3- and 5-year survival prediction reached 0.76, 0.84 and 0.84, respectively, indicating that this model has a high accuracy. Finally, the difference between high-risk group and low-risk group were investigated using multi-omics data including gene expression, DNA methylation and somatic mutations. Our study provides significant clues for the elucidation of eRNAs in STAD and may help improve the overall survival for STAD patients.
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Affiliation(s)
- Liuying Gao
- The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China. .,Department of Preventive Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo, 315211, China.
| | - Hao Rong
- The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, China.,Department of Preventive Medicine, Zhejiang Provincial Key Laboratory of Pathological and Physiological Technology, School of Medicine, Ningbo, 315211, China
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Gao DZ, Yang YS, Wang Z, Zhao XF. Expression profile and prognostic significance of HOXB13 in rectal cancer. Int J Biol Markers 2022; 37:140-148. [PMID: 35296171 DOI: 10.1177/17246008221076151] [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] [Indexed: 11/16/2022]
Abstract
BACKGROUND This study aimed to investigate the expression pattern and prognostic significance of HOXB13 in rectal cancer. METHODS HOXB13 expression in rectal cancer and normal adjacent tissues was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, and its clinicopathological characteristics and prognosis were statistically tested. Furthermore, we evaluated the association between tumor immune infiltrating cells and HOXB13 using the tumor immune estimation resource (TIMER) database. The potential biological mechanism associated with HOXB13 overexpression was investigated by gene set enrichment analysis (GSEA). RESULTS The expression of HOXB13 messenger RNA and protein in human rectal cancer tissues were significantly higher than those in the normal adjacent tissues (P < 0.05). HOXB13 expression was significantly correlated with depth of invasion, lymphatic invasion, lymph node metastasis, distant metastasis, and pathological tumor node metastasis stage (P < 0.05). Kaplan-Meier survival curves confirmed that HOXB13 overexpression was correlated negatively with overall survival and disease-free survival in rectal cancer (P < 0.05). Also, multivariate Cox regression analysis demonstrated that HOXB13 expression, age, and lymphatic invasion were independent prognostic factors in rectal cancer (P < 0.05). Plus, the results from the TIMER database indicated that HOXB13 expression has a significant association with several immune cell infiltrates. Finally, the GSEA results indicated that HOXB13 participated in the various immune-associated processes, including natural killer cell-mediated cytotoxicity and the T-cell receptor signaling pathway. CONCLUSION Our study showed an essential role of HOXB13 in rectal cancer immunity and prognosis. Significantly, the overexpression of HOXB13 leads to the worse prognosis for patients with rectal cancer, which will contribute to understanding molecular mechanisms associated with tumor pathogenesis and prognosis in this disease.
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Affiliation(s)
- Da-Zhi Gao
- Department of General Surgery, 194043Dalian University Affiliated Xinhua Hospital, Dalian 116021, China
| | - Yu-Shen Yang
- Department of General Surgery, 194043Dalian University Affiliated Xinhua Hospital, Dalian 116021, China
| | - Zhun Wang
- Department of General Surgery, 194043Dalian University Affiliated Xinhua Hospital, Dalian 116021, China
| | - Xue-Feng Zhao
- Department of General Surgery, 194043Dalian University Affiliated Xinhua Hospital, Dalian 116021, China
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Shenoy US, Adiga D, Kabekkodu SP, Hunter KD, Radhakrishnan R. Molecular implications of HOX genes targeting multiple signaling pathways in cancer. Cell Biol Toxicol 2022; 38:1-30. [PMID: 34617205 PMCID: PMC8789642 DOI: 10.1007/s10565-021-09657-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/10/2021] [Indexed: 11/17/2022]
Abstract
Homeobox (HOX) genes encode highly conserved homeotic transcription factors that play a crucial role in organogenesis and tissue homeostasis. Their deregulation impacts the function of several regulatory molecules contributing to tumor initiation and progression. A functional bridge exists between altered gene expression of individual HOX genes and tumorigenesis. This review focuses on how deregulation in the HOX-associated signaling pathways contributes to the metastatic progression in cancer. We discuss their functional significance, clinical implications and ascertain their role as a diagnostic and prognostic biomarker in the various cancer types. Besides, the mechanism of understanding the theoretical underpinning that affects HOX-mediated therapy resistance in cancers has been outlined. The knowledge gained shall pave the way for newer insights into the treatment of cancer.
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Affiliation(s)
- U Sangeetha Shenoy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Keith D Hunter
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, S10 2TA, UK
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India.
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Tumor-promoting function of PIMREG in glioma by activating the β-catenin pathway. 3 Biotech 2021; 11:380. [PMID: 34458056 DOI: 10.1007/s13205-021-02922-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 07/13/2021] [Indexed: 10/20/2022] Open
Abstract
Glioma is the most common primary brain tumor in adults with an adverse prognosis and obscure pathogenesis. PICALM interacting mitotic regulator protein (PIMREG) functions as an oncogene in multiple types of cancer, but its function in glioma remains unknown. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2, http://gepia2.cancer-pku.cn/#index) showed that PIMREG expression in the glioma tissues was higher than that in normal brain tissues. Herein, cell counting kit-8 assay and flow cytometry analysis exhibited that overexpression of PIMREG significantly promoted the proliferation of glioma cells and the transition from G1 phase of the cell cycle to S phase. Wound-healing and transwell assays showed that overexpression of PIMREG markedly enhanced the migration and invasion of glioma cells. Western blot analysis revealed that overexpression of PIMREG increased the expression of cyclin D1, cyclin E, Vimentin, matrix metalloproteinase (MMP)-2, and MMP-9, but reduced the expression of E-cadherin. In addition, overexpression of PIMREG activated the β-catenin signaling pathway, as evidenced by the increased total and nuclear expression of β-catenin and the up-regulated expression of its downstream target c-myc. Furthermore, immunofluorescence staining further indicated the increased nuclear translocation of β-catenin in PIMREG-overexpressing cells. However, knockdown of PIMREG exerted opposite effects on glioma cells. Blockade of the β-catenin signaling by ICG-001 markedly impeded the promoting effects of PIMREG on glioma cell proliferation and invasion. In conclusion, PIMREG acts as a tumor promoter in glioma at least partly via activating the β-catenin signaling pathway. This study provides new insights into the molecular mechanism for glioma pathogenesis and treatment.
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Xin Z, Zhang L, Liu M, Wang Y, Zhang Y, Zhao W, Sun Y, Shi L, Xu N, Zhang N, Xu H. Helicobacter pylori Infection-Related Long Non-Coding RNA Signatures Predict the Prognostic Status for Gastric Cancer Patients. Front Oncol 2021; 11:709796. [PMID: 34386426 PMCID: PMC8353258 DOI: 10.3389/fonc.2021.709796] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/06/2021] [Indexed: 12/24/2022] Open
Abstract
Background Helicobacter pylori (H. pylori) is a type I biological carcinogen, which may cause about 75% of the total incidence of gastric cancer worldwide. H. pylori infection can induce and activate the cancer-promoting signaling pathway and affect the occurrence and outcome of gastric cancer through controlling the regulatory functions of long non-coding RNAs (lncRNAs). However, we have no understanding of the prognostic worth of lncRNAs for gastric cancer patients infected with H. pylori. Method We screened differentially expressed lncRNAs using DESeq2 method among TCGA database. And we built the H. pylori infection-related lncRNAs regulatory patterns. Then, we constructed H. pylori infection-based lncRNAs prognostic signatures for gastric cancer patients together with H. pylori infection, via uni-variable and multi-variable COX regression analyses. Based on receiver operator characteristic curve (ROC) analysis, we evaluated the prediction effectiveness for this model. Results We identified 115 H. pylori infection-related genes were differentially expressed among H. pylori-infected gastric cancer tissues versus gastric cancer tissues. Functional enrichment analysis implies that H. pylori infection might interfere with the immune-related pathways among gastric cancer tissues. Then, we built H. pylori infection-related dys-regulated lncRNA regulatory networks. We also identified 13 differentially expressed lncRNAs were associated with prognosis for gastric cancer patients together with H. pylori infection. Kaplan-Meier analysis demonstrated that the lncRNA signatures were correlated with the poor prognosis. What is more, the AUC of the lncRNA signatures was 0.712. Also, this prognostic prediction model was superior to the traditional clinical characters. Conclusion We successfully constructed a H. pylori-related lncRNA risk signature and nomogram associated with H. pylori-infected gastric cancer patients prognosis, and the signature and nomogram can predict the prognosis of these patients.
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Affiliation(s)
- Zhuoyuan Xin
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China.,The Key Laboratory of Zoonosis Research, Chinese Ministry of Education, College of Basic Medical Science, Jilin University, Changchun, China.,Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Luping Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Mingqing Liu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yachen Wang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yingli Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Weidan Zhao
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Yongxiao Sun
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Lei Shi
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Na Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Nan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Hong Xu
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Tang Y, Wang T, Yu Y, Yan Y, Wu C. Upregulation of HOXC9 generates interferon-gamma resistance in gastric cancer by inhibiting the DAPK1/RIG1/STAT1 axis. Cancer Sci 2021; 112:3455-3468. [PMID: 34159686 PMCID: PMC8409412 DOI: 10.1111/cas.15043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/28/2021] [Accepted: 06/19/2021] [Indexed: 12/14/2022] Open
Abstract
Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 (HOXC9) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon‐gamma (IFNγ)‐dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase‐3/7 and phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death‐associated protein kinase 1 (DAPK1) and its downstream retinoic acid‐inducible gene‐I (RIG1) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p‐STAT1 axis.
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Affiliation(s)
- Yuanxin Tang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Taifang Wang
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yue Yu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuhao Yan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunli Wu
- Department of Radiation Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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