Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis

Peng Xu,Kang Hu,Ping Zhang,Zhi-Gang Sun,Nan Zhang

doi:10.1186/s12935-021-02368-y

Peng Xu, Kang Hu + Show 3 more

Open Access

https://doi.org/10.1186/s12935-021-02368-y

Copy DOI

Abstract

BackgroundN6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive.MethodsThe knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells.ResultsThe results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN– 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients.ConclusionIn brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

Highlights

Worldwide, malignant tumors of the lung are the primary cause of cancer incidence and death, ranking as the highest tumor-related mortality with more than 1.8 million deaths in 2018 and accounting for almost 1 in 5Xu et al Cancer Cell International (2022) 22:13The cellular response to hypoxia, followed by activation of hypoxia-inducible factor 1 (HIF-1), has been reported to be emerging as an important mechanism promoting tumor aggressiveness, metastasis, and poor prognosis [5]
The stable YTH domain family 2 (YTHDF2) upregulation models were established in NCI-H226 and SK-MES-1 cells to explore the biological function of YTHDF2 in lung squamous cell carcinoma (LUSC)
YTHDF2 overexpression upregulates the protein levels of P‐AKT and P‐mTOR and induces Epithelial-mesenchymal transition (EMT) in LUSC cells We investigated whether YTHDF2 overexpression activates key signaling pathways in LUSC cells, such as the ERK/MAPK and mTOR/AKT signaling pathways known to play a role in tumor proliferation and survival

Summary

Introduction

Malignant tumors of the lung are the primary cause of cancer incidence and death, ranking as the highest tumor-related mortality with more than 1.8 million deaths in 2018 and accounting for almost 1 in 5Xu et al Cancer Cell International (2022) 22:13The cellular response to hypoxia, followed by activation of hypoxia-inducible factor 1 (HIF-1), has been reported to be emerging as an important mechanism promoting tumor aggressiveness, metastasis, and poor prognosis [5]. N6-methyadenosine (m6A), the most prevalent modification of mRNA, is induced by hypoxia and promotes cancer progression, angiogenesis, and metastasis in several cancers [6, 7], but is widely involved in many biological processes, such as splicing and stability of mRNA, RNA nucleation, the interaction between RNA and protein, and protein translation [8,9,10]. M6A RNA modification acts as a dynamic and reversible internal RNA modification process promoted by a ‘writer’ complex (METTL3, METTL14, WTAP, and other undiscovered subunits), inhibited by ‘erasers’ (FTO and ALKBH5), and functionally executed by ‘readers’ (the YTH domain-containing family (YTHDF1-3, YTHDC1-2) and HNRNP family proteins) [12,13,14]. The biological functions of m6A modification in mRNA have been reported to contribute to regulating the progression of cancer development [22,23,24]. The function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive

Methods

Results

Conclusion