AK2 Promotes the Migration and Invasion of Lung Adenocarcinoma by Activating TGF-β/Smad Pathway In vitro and In vivo.

Fangfang Cai,Xiaoyao Chang,Ping Li,Yingying Yao,Huangru Xu,Zi-Chun Hua,Xiaoyang Wang,Yanyan Lu,Shihui Yu,Daolong Zha,Jia Chen,Hongqin Zhuang

doi:10.3389/fphar.2021.714365

Fangfang Cai, Xiaoyao Chang + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2021.714365

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Abstract

Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.

Highlights

Lung cancer is the leading cause of cancer-related mortality worldwide, with a poor 5-year survival rate of 15% (Siegel et al, 2018), among which non-small cell lung carcinoma (NSCLC) accounts for 75–80% of this disease (Meza et al, 2015)
We found that Adenylate kinase 2 (AK2) was almost undetectable in normal lung tissues, while its expression level in lung cancer tissues gradually increased with the progresses of cancer (Figure 1A)
Bioinformatic analysis showed that AK2 expression levels significantly increased in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) than that in normal tissues (Figure 1C), and the p-values were all less than 0.0001

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide, with a poor 5-year survival rate of 15% (Siegel et al, 2018), among which non-small cell lung carcinoma (NSCLC) accounts for 75–80% of this disease (Meza et al, 2015). There are multiple treatment options including surgery, chemotherapy, radiation and targeted therapy, the prognosis of patients is still poor due to its high metastasis (Altorki et al, 2019). Tumor metastasis is a complex process involving a series of cell activities, collectively referred to as the invasion-metastasis cascade process (Valastyan and Weinberg, 2011). Many studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in tumor cell infiltration, migration and metastasis. It enhances cancer cell invasion and metastasis (Mani et al, 2008; Kalluri and Weinberg, 2009), and enables them to acquire stem cell characteristics such as self-renewal, and AK2 Promotes Migration and Invasion promote cancer stem cell production. The complex enters the nucleus and interacts with DNA, up-regulating the expression levels of transcription factors Snail/Slug, Twist and ZEB1, down-regulating the expression levels of E-cadherin, thereby regulating EMT at the transcriptional level (Vincent et al, 2009; Lamouille et al, 2014)

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