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Nature: circRNA regulates non-small cell lung cancer

Nature: circRNA regulates non-small cell lung cancer. Nature Sub-Journal: Reveal the new mechanism of circRNA regulating the progression of non-small cell lung cancer.

Lung cancer is one of the most common malignant tumors in the world. There are about 1.8 million new cases of lung cancer each year and 1.6 million deaths worldwide.

Lung cancer is one of the most common malignant tumors in the world. There are about 1.8 million new cases of lung cancer each year and 1.6 million deaths worldwide. In China, there are about 820,000 new cases of lung cancer each year, and the death toll is as high as 710,000. Lung cancer mainly includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Among them, non-small cell lung cancer accounts for about 85% of all diagnosed lung cancer cases. Although targeted therapy and immunotherapy have achieved certain curative effects, the 5-year survival rate of patients with non-small cell lung cancer is still less than 20%. Therefore, in-depth research on the occurrence and development of non-small cell lung cancer and the discovery of potential molecular targets for the treatment of non-small cell lung cancer have important clinical significance.

The results published in the Encyclopedia of DNA Elements (ENCODE) completed in 2012 show that about 80% of the sequences in the human genome will be transcribed into RNA, of which only about 2% of the mRNA encoding the protein, and the remaining sequences It is transcribed into a variety of regulatory RNA molecules. Among them, circular RNAs (circular RNAs, circRNAs) are single-stranded RNA molecules that do not have a 5’cap and a 3’poly(A) tail, and form a circular structure by covalent bonds.

In 1991, it was reported in the literature that circRNAs exist in humans and mice, but due to their low expression abundance and a small number of discoveries, they were once considered to be caused by incorrect splicing or splicing of pre-mRNAs As a by-product, it has not attracted people’s attention. In recent years, with high-throughput sequencing technology for sequencing samples without poly(A) RNA transcriptome and linear RNA digested with ribonuclease R (RNase R), it has been found that circRNAs are widely present in cells.

The special structure of the closed loop of circRNAs gives it high stability, making it a RNA molecule with a long half-life. Therefore, although the production efficiency of circRNAs is low at the transcription level, they can reach higher abundance through accumulation. In recent years, more and more studies have shown that circRNAs are widely involved in the occurrence and development of tumors. However, the role and mechanisms of circRNAs in the progression of non-small cell lung cancer are still poorly understood.

On January 12, 2021, researcher Qin Wenxin from Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, and Professor Jiang Liyan from Shanghai Chest Hospital, Shanghai Jiaotong University, published the title: circNDUFB2 inhibits non- in Nature Communications. small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity
Research papers.

This study was the first to explore the function and mechanism of circNDUFB2 in the development of non-small cell lung cancer through high-throughput screening of circRNAs expression profiles in cancer and adjacent tissues of non-small cell lung cancer.

This is also the case that Qin Wenxin/Jiang Liyan team collaborated in 2019 to discover that circTP63 acts as a ceRNA to competitively bind miR-873-3p to up-regulate FOXM1 and promote lung squamous cell carcinoma proliferation (Nat. Commun. 2019). In 2020, it was discovered that circFOXM1 up-regulated FAM38D through competitively binding miR-614 Another discovery after promoting the progression of non-small cell lung cancer (J. Exp. Clin. Cancer Res. 2020).

In this study, the authors first used circular RNA expression profiling chips to analyze the differentially expressed circular RNA molecules in the cancer and paracancerous tissues of 3 patients with non-small cell lung cancer. The first 5 circRNAs molecules with the most significant differential expression in the results of microarray screening were verified in the para-cancerous tissues, and the circNDUFB2 with the most significant difference was finally screened as a candidate molecule for subsequent functional research and mechanism exploration.

circNDUFB2 is lowly expressed in non-small cell lung cancer tissues, and its expression is negatively correlated with the patient’s tumor size, lymph node metastasis and stage. Cell function experiments showed that circNDUFB2 significantly inhibited cell proliferation and metastasis of non-small cell lung cancer. Mouse subcutaneous tumor formation experiments and lung metastasis experiments also confirmed that circNDUFB2 inhibited tumor growth and metastasis. The above experiments show that circNDUFB2 may be used as a tumor suppressor to inhibit the progression of non-small cell lung cancer.

As a competitive endogenous RNA (ceRNA), circRNAs competitively bind to miRNA, and regulate the stability of target gene mRNA has been extensively studied. The author’s analysis found that circNDUFB2 does not bind to the Ago2 protein, indicating that circNDUFB2 is not involved in regulating the progression of non-small cell lung cancer through the ceRNA mechanism. Subsequently, the author found through RNA pulldown experiment and mass spectrometry analysis that circNDUFB2 binds to the oncofetal protein IGF2BPs and reduces its protein stability.

Further research found that circNDUFB2 as a scaffold strengthens the binding of E3 ubiquitin ligase TRIM25 to IGF2BPs and promotes the ubiquitination and degradation of IGF2BPs, and the m6A modification of circNDUFB2 helps to strengthen the combination of TRIM25 and IGF2BPs and the degradation of IGF2BPs. In addition, the authors found that although the circNDUFN2 mutant cannot reduce the stability of IGF2BPs, it still has a certain inhibitory effect on the proliferation and metastasis of non-small cell lung cancer. This suggests that in addition to promoting the degradation of IGF2BPs, circNDUFB2 may also inhibit the progression of non-small cell lung cancer through other mechanisms.

In order to further explore the signaling pathways involved in circNDUFB2, the authors analyzed the genes and the signaling pathways involved in the overexpression of circNDUFB2 and the differentially expressed in A549 cells of the control group, and found that circNDUFB2 activated the immune defense response. circNDUFB2 binds to the nucleic acid recognition protein RIG-I and activates the RIG-I-MAVS signaling pathway, releases IFNβ and a variety of chemokines, and induces immune cell infiltration in the tumor microenvironment, thereby inhibiting the progression of non-small cell lung cancer.

Nature: circRNA regulates non-small cell lung cancer
circNDUFB2 inhibits the progression of non-small cell lung cancer

This study not only systematically screened the expression profile of circRNAs in non-small cell lung cancer tissues, but also explained in-depth the molecular mechanism of circNDUFB2 in promoting the ubiquitination and degradation of IGF2BPs and activating anti-tumor immunity. It is important for circRNAs to regulate the progression of non-small cell lung cancer. Functions and mechanisms provide new insights.

Doctoral students Li Botai and Zhu Lili of the State Key Laboratory of Oncogenes and Related Genes and Deputy Chief Physician Lu Chunlai of Zhongshan Hospital of Fudan University are the co-first authors of this article; Professor Qin Wenxin and Professor Jiang Liyan are the co-corresponding authors of this article.