Pan-cancer analysis of HS6ST2: associations with prognosis, tumor immunity, and drug resistance

Luxin Huang; Sidra Irshad; Ulfat Sultana; Saqib Ali; Ayesha Jamil; Ayesha Zubair; Rizwana Sultan; Mostafa A Abdel-Maksoud; Ayman Mubarak; Bandar M Almunqedhi; Taghreed N Almanaa; Abdul Malik; Abdulaziz Alamri; Ahmad S Kodous; Mohammed Mares; Mohamed Y Zaky; Syeda Saba Sajjad; Yasir Hameed

doi:10.62347/NCPH5416

Pan-cancer analysis of HS6ST2: associations with prognosis, tumor immunity, and drug resistance

Am J Transl Res. 2024 Mar 15;16(3):873-888. doi: 10.62347/NCPH5416. eCollection 2024.

Authors

Luxin Huang¹, Sidra Irshad², Ulfat Sultana², Saqib Ali³, Ayesha Jamil⁴, Ayesha Zubair⁵, Rizwana Sultan⁶, Mostafa A Abdel-Maksoud⁷, Ayman Mubarak⁷, Bandar M Almunqedhi⁷, Taghreed N Almanaa⁷, Abdul Malik⁸, Abdulaziz Alamri⁹, Ahmad S Kodous^{10

11}, Mohammed Mares¹², Mohamed Y Zaky¹³, Syeda Saba Sajjad¹⁴, Yasir Hameed¹⁵

Affiliations

¹ Department of Gynecology, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University Jinan 250000, Shandong, China.
² Department of Pharmacology, Muhammad College of Medicine Peshawar 25000, Pakistan.
³ Department of Computer Science, University of Agriculture Faisalabad 38000, Pakistan.
⁴ Department of Pharmacology, Khyber Girls Medical College Peshawar 25000, Pakistan.
⁵ CMH Lahore Medical College and Institute of Dentistry Lahore 54000, Pakistan.
⁶ Department of Pathology, Faculty of Veterinary and Animal Sciences, Cholistan University of Veterinary and Animal Sciences Bahawalpur 63100, Pakistan.
⁷ Department of Botany and Microbiology, College of Science, King Saud University P.O. Box 2455, Riyadh 11451, Saudi Arabia.
⁸ Department of Pharmaceutics, College of Pharmacy, King Saud University Saudi Arabia.
⁹ Department of Biochemistry, College of Science King Saud University Saudi Arabia.
¹⁰ Department of Molecular Oncology, Cancer Institute (WIA) 38, Sardar Patel Road, Chennai, P.O. Box 600036, Tamilnadu, India.
¹¹ Department of Radiation Biology, National Center for Radiation Research & Technology (NCRRT), Egyptian Atomic-Energy Authority (EAEA) Egypt.
¹² Department of Zoology, College of Science King Saud University Saudi Arabia.
¹³ UPMC Hillman Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of Pittsburgh Pittsburgh, PA 15213, USA.
¹⁴ Pakistan Institute of Medical Sciences Islamabad 46000, Pakistan.
¹⁵ Department of Biotechnology, Institute of Biochemistry Biotechnology, and Bioinformatics, The Islamia University of Bahawalpur Bahawalpur 63100, Pakistan.

Abstract

Objectives: In this comprehensive study spanning 33 malignancies, we explored the differential expression and prognostic significance of Heparan sulfate 6-O-sulfotransferase 2 (HS6ST2).

Methods: TIMER2, UALCAN, and GEPIA2 were used for the expression analysis. cBioPortal was used for mutational analysis. CancerSEA, STRING, and DAVID, were employed for the single cell sequencing data analysis, protein-protein interaction network development, and gene enrichment analyses, respectively. GSCAlite and RT-qPCR were used for drug sensitivity and expression validation analysis.

Results: HS6ST2 exhibited significant (P < 0.05) overexpression in multiple cancers. Prognostically, elevated HS6ST2 expression was significantly associated with poor overall survival (OS) in patients with cervical squamous cell carcinoma (CESC), kidney chromophobe (KICH), lung adenocarcinoma (LUAD), and stomach adenocarcinoma (STAD), emphasizing its potential as a prognostic indicator in these cancers. Moreover, HS6ST2 expression correlated with pathological stages in CESC, KICH, LUAD, and STAD patients. Exploration of genetic alterations using cBioPortal unveiled distinct mutational landscapes, with low mutation frequencies in CESC, KICH, LUAD, and STAD. Additionally, reduced DNA methylation in CESC, KICH, LUAD, and STAD suggested a potential link between hypomethylation and heightened HS6ST2 expression. Analysis of immune cell infiltration revealed a positive correlation between HS6ST2 expression and the infiltration of CD8+ T and CD4+ T cells in CESC, KICH, LUAD, and STAD, highlighting its involvement in the tumor immunology processes. Single-cell functional states analysis demonstrated associations between HS6ST2 and diverse cellular processes. Moreover, gene enrichment analysis revealed the involvement HS6ST2 in crucial cellular activities. GSCAlite analysis underscored the potential of HS6ST2 as a therapeutic target, showing associations with drug sensitivity. Finally, experimental validation through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in LUAD tissues confirmed elevated HS6ST2 expression.

Conclusion: Overall, this study provides a comprehensive understanding of HS6ST2 in CESC, KICH, LUAD, and STAD, emphasizing its potential as a prognostic biomarker and therapeutic target.

Keywords: Cancer; HS5ST2; prognosis; therapeutic target.