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Theranostics 2022; 12(17):7267-7288. doi:10.7150/thno.76689 This issue Cite

Research Paper

N6-methyladenosine-associated prognostic pseudogenes contribute to predicting immunotherapy benefits and therapeutic agents in head and neck squamous cell carcinoma

Liqiang Tan^1,2,3, Yali Qin⁴, Ruiling Xie^1,2,3, Tianliang Xia^1,2,3, Xiaotong Duan^1,2,3, Lan Peng^1,2,3, Rui You^1,2,3, Youping Liu^1,2,3, Xiong Zou^1,2,3, Mengxia Zhang^1,2,3, Mei Lin^1,2,3, Mingyuan Chen^1,2,3✉

1. Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, No.651 Dongfeng East Road, Guangzhou 510060, China.
2. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
3. Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, China.
4. Department of Ophthalmology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.

✉ Corresponding author: Dr. Mingyuan Chen, Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, No.651 Dongfeng East Road, Guangzhou 510060, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, No.651 Dongfeng East Road, Guangzhou 510060, China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, No.651 Dongfeng East Road, Guangzhou 510060, China. Tel: +86-20-87343361; Fax: +86-20-87343624; E-mail: chmingysysu.edu.cn. More

Abstract

Rationale: N6-methyladenosine (m⁶A) is involved in critical cancerous processes. Pseudogenes play various roles in carcinogenesis and progression. However, the functional roles of m⁶A-associated pseudogenes in head and neck squamous cell carcinoma (HNSCC) are largely unknown.

Methods: We systematically analyzed the mRNA profile of 24 m⁶A regulators and 13931 pseudogenes from The Cancer Genome Atlas HNSCC dataset and ultimately identified 10 m⁶A-associated prognostic pseudogenes, which were validated in the Gene Expression Omnibus and our hospital datasets. Based on the risk score of m⁶A-associated pseudogenes, comprehensive analytical frameworks and experimental validation were implemented among pseudogene-defined low-/high-risk subtypes.

Results: Here, we found expression pattern of m⁶A-associated pseudogenes was significantly associated with infiltrating immune cell compositions, and the expression of antitumor immune response markers, including T cell exhaustion, antigen presentation, interferon, and kinase genes. The m⁶A-associated pseudogenes, which had dramatic m⁶A peaks and higher m⁶A levels, could regulate the expression of targeted immune-involved genes through miRNAs. We experimentally validate the oncogene PDIA3P1, and tumor-suppressor RRN3P3, which promote the RNA and protein expression of their targeted immune-involved genes AKT1 and EZH2 via miR-34a-5p and miR-26b-5p, respectively. Moreover, HNSCC patients in the high-risk subtype could benefit more from immune checkpoint inhibitors therapy. Furthermore, doxorubicin and topotecan were considered to hold the most promising therapeutic potential robustly in silico evidence and in vitro experiments for HNSCC patients in the high-risk subtype.

Conclusions: Our discovery revealed that the 10 m⁶A-associated prognostic pseudogenes significantly contribute to predicting immunotherapy benefits and therapeutic agents, which might bring some potential implications for both immunotherapy and chemotherapy in HNSCC.

Keywords: N6-methyladenosine, Pseudogene, Immunotherapy benefits, Therapeutic agents, Head and neck squamous cell carcinoma

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