P53-associated lncRNAs regulate immune functions and RNA-modifiers in gastric cancer

Zhao Huanjie; Ihtisham Bukhari; Li Fazhan; Huijuan Wen; Jingyun Wang; Wu Wanqing; Fu Yuming; Tang Youcai; Reem M AlJowaie; Ibrahim M Aziz; Chu Xiufeng; Mi Yang; Zheng Pengyuan

doi:10.1016/j.heliyon.2024.e35228

P53-associated lncRNAs regulate immune functions and RNA-modifiers in gastric cancer

Heliyon. 2024 Jul 26;10(15):e35228. doi: 10.1016/j.heliyon.2024.e35228. eCollection 2024 Aug 15.

Authors

Zhao Huanjie¹, Ihtisham Bukhari^{1

2}, Li Fazhan¹, Huijuan Wen¹, Jingyun Wang^{1

2}, Wu Wanqing³, Fu Yuming³, Tang Youcai⁴, Reem M AlJowaie⁵, Ibrahim M Aziz⁵, Chu Xiufeng⁶, Mi Yang^{1

2

7

8}, Zheng Pengyuan^{1

2

7

8}

Affiliations

¹ Henan Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, ErQi 450052, Zhengzhou, Henan, China.
² Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, ErQi, 450052, Zhengzhou, Henan, China.
³ Department of Gastrointestinal Surgery, the Fifth Affiliated Hospital of Zhengzhou University, ErQi, 450052, Zhengzhou, Henan, China.
⁴ Department of Pediatrics, the Fifth Affiliated Hospital of Zhengzhou University, ErQi, 450052, Zhengzhou, Henan, China.
⁵ Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.
⁶ Department of Oncology, the Fifth Affiliated Hospital of Zhengzhou University, ErQi, 450052, Zhengzhou, Henan, China.
⁷ Academy of Medical Science, Zhengzhou University, Zhongyuan, 450001, Zhengzhou, Henan China, China.
⁸ Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Sciences, Zhengzhou, Henan, China.

Abstract

TP53, a guardian of the genome, suppresses or enhances tumors through various regulatory pathways. However, the role of p53-related long non-coding RNAs (lncRNAs) in immune regulation of tumor microenvironment and prognosis of gastric cancer (GC) is so far unelucidated. We analyzed the role of TP53-associated lncRNAs (obtained from the TP53LNC-DB database) in immune regulation, immune cell infiltration and RNA modification in gastric cancer. Firstly, using multivariate COX regression analysis, we identified eight lncRNAs related to the prognosis of GC. Furthermore, based on the expression of the lncRNA signature and risk score, the GC patients were divided into high-risk and low-risk groups. We found that M2-macrophages have significantly higher infiltration in the high-risk group. Similarly, significant differences in immune function (APC_co_stimulation, CCR, and checkpoint) and m⁶A modification (FTO, ZC3H13, YTHDC1, and RBM15), and m⁵C modification (NOP2 and TET1) between both groups were also observed. These signature lncRNAs were also positively associated with oxidative stress-related genes (MPO, MAPK14, HMOX1, and APP). Additionally, we found that high expression of GAS5 and low expression of MALAT1 in Helicobacter pylori (H-pylori) positive GC patients. Finally, GC patients in the low-risk group showed higher resistance to immunotherapy while patients in the high-risk group were more sensitive to various chemotherapy drugs. Based on these findings, we conclude that p53-associated lncRNAs signature could potentially predict the immune status and overall survival, and may also be used for risk management and planning immunotherapy for gastric cancer patients.

Keywords: Gastric cancer; Immune cell infiltration; Immunotherapy; P53-related lncRNAs; Tumor microenvironment; lncRNA signature; m5C; m6A.