Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration

Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, n...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Bashir Lawal, Yu-Cheng Kuo, Sung-Ling Tang, Feng-Cheng Liu, Alexander T. H. Wu, Hung-Yun Lin, Hsu-Shan Huang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cholangiocarcinoma tumor microenvironment therapeutic resistance receptor-ligand interaction molecular docking CHOL-hub gene Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c50411c8735f464bb34f797892f3c59d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c50411c8735f464bb34f797892f3c59d
record_format	dspace
spelling	oai:doaj.org-article:c50411c8735f464bb34f797892f3c59d2021-11-25T17:08:22ZTranscriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration10.3390/cells101128732073-4409https://doaj.org/article/c50411c8735f464bb34f797892f3c59d2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2873https://doaj.org/toc/2073-4409Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, necessitating the need for further evaluation of the genome and RNA expression data in order to identify potential therapeutic targets, clarify the roles of these targets in the tumor microenvironment, and explore novel therapeutic drugs against the identified targets. Consequently, in our attempt to explore novel genetic markers associated with the carcinogenesis of CHOL, five genes (<i>SNX15</i>, <i>ATP2A1</i>, <i>PDCD10</i>, <i>BET1</i>, and <i>HMGA2</i>), collectively termed CHOL-hub genes, were identified via integration of differentially expressed genes (DEGs) from relatively large numbers of samples from CHOL GEO datasets. We further explored the biological functions of the CHOL-hub genes and found significant enrichment in several biological process and pathways associated with stem cell angiogenesis, cell proliferation, and cancer development, while the interaction network revealed high genetic interactions with a number of onco-functional genes. In addition, we established associations between the CHOL-hub genes and tumor progression, metastasis, tumor immune and immunosuppressive cell infiltration, dysfunctional T-cell phenotypes, poor prognoses, and therapeutic resistance in CHOL. Thus, we proposed that targeting CHOL-hub genes could be an ideal therapeutic approach for treating CHOLs, and we explored the potential of HLC-018, a novel benzamide-linked small molecule, using molecular docking of ligand-receptor interactions. To our delight, HLC-018 was well accommodated with high binding affinities to binding pockets of CHOL-hub genes; more importantly, we found specific interactions of HLC-018 with the conserved sequence of the AT-hook DNA-binding motif of <i>HMGA2</i>. Altogether, our study provides insights into the immune-oncogenic phenotypes of CHOL and provides valuable information for our ongoing experimental validation.Bashir LawalYu-Cheng KuoSung-Ling TangFeng-Cheng LiuAlexander T. H. WuHung-Yun LinHsu-Shan HuangMDPI AGarticlecholangiocarcinomatumor microenvironmenttherapeutic resistancereceptor-ligand interactionmolecular dockingCHOL-hub geneBiology (General)QH301-705.5ENCells, Vol 10, Iss 2873, p 2873 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cholangiocarcinoma tumor microenvironment therapeutic resistance receptor-ligand interaction molecular docking CHOL-hub gene Biology (General) QH301-705.5
spellingShingle	cholangiocarcinoma tumor microenvironment therapeutic resistance receptor-ligand interaction molecular docking CHOL-hub gene Biology (General) QH301-705.5 Bashir Lawal Yu-Cheng Kuo Sung-Ling Tang Feng-Cheng Liu Alexander T. H. Wu Hung-Yun Lin Hsu-Shan Huang Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
description	Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, necessitating the need for further evaluation of the genome and RNA expression data in order to identify potential therapeutic targets, clarify the roles of these targets in the tumor microenvironment, and explore novel therapeutic drugs against the identified targets. Consequently, in our attempt to explore novel genetic markers associated with the carcinogenesis of CHOL, five genes (<i>SNX15</i>, <i>ATP2A1</i>, <i>PDCD10</i>, <i>BET1</i>, and <i>HMGA2</i>), collectively termed CHOL-hub genes, were identified via integration of differentially expressed genes (DEGs) from relatively large numbers of samples from CHOL GEO datasets. We further explored the biological functions of the CHOL-hub genes and found significant enrichment in several biological process and pathways associated with stem cell angiogenesis, cell proliferation, and cancer development, while the interaction network revealed high genetic interactions with a number of onco-functional genes. In addition, we established associations between the CHOL-hub genes and tumor progression, metastasis, tumor immune and immunosuppressive cell infiltration, dysfunctional T-cell phenotypes, poor prognoses, and therapeutic resistance in CHOL. Thus, we proposed that targeting CHOL-hub genes could be an ideal therapeutic approach for treating CHOLs, and we explored the potential of HLC-018, a novel benzamide-linked small molecule, using molecular docking of ligand-receptor interactions. To our delight, HLC-018 was well accommodated with high binding affinities to binding pockets of CHOL-hub genes; more importantly, we found specific interactions of HLC-018 with the conserved sequence of the AT-hook DNA-binding motif of <i>HMGA2</i>. Altogether, our study provides insights into the immune-oncogenic phenotypes of CHOL and provides valuable information for our ongoing experimental validation.
format	article
author	Bashir Lawal Yu-Cheng Kuo Sung-Ling Tang Feng-Cheng Liu Alexander T. H. Wu Hung-Yun Lin Hsu-Shan Huang
author_facet	Bashir Lawal Yu-Cheng Kuo Sung-Ling Tang Feng-Cheng Liu Alexander T. H. Wu Hung-Yun Lin Hsu-Shan Huang
author_sort	Bashir Lawal
title	Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
title_short	Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
title_full	Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
title_fullStr	Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
title_full_unstemmed	Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration
title_sort	transcriptomic-based identification of the immuno-oncogenic signature of cholangiocarcinoma for hlc-018 multi-target therapy exploration
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c50411c8735f464bb34f797892f3c59d
work_keys_str_mv	AT bashirlawal transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT yuchengkuo transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT sunglingtang transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT fengchengliu transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT alexanderthwu transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT hungyunlin transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration AT hsushanhuang transcriptomicbasedidentificationoftheimmunooncogenicsignatureofcholangiocarcinomaforhlc018multitargettherapyexploration
_version_	1718412740518739968

Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration

Ejemplares similares