MIR22HG As A Tumor Suppressive lncRNA In HCC: A Comprehensive Analysis Integrating RT-qPCR, mRNA-Seq, And Microarrays

Li Gao,1,* Dan-dan Xiong,1,* Rong-quan He,2 Xia Yang,1 Ze-feng Lai,3 Li-min Liu,3 Zhi-guang Huang,1 Hua-yu Wu,4 Li-hua Yang,2 Jie Ma,2 Sheng-hua Li,5 Peng Lin,6 Hong Yang,6 Dian-zhong Luo,1 Yi-wu Dang,1,* Gang Chen1,* 1Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China; 2Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China; 3School of Pharmacy, Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China; 4Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China; 5Department of Urology Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China; 6Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, Zhuang Autonomous Region 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gang ChenDepartment of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi 530021, People’s Republic of ChinaTel +0086-771-5356534Fax +86 0771-5356534Email chengang@gxmu.edu.cnYi-wu DangDepartment of Pathology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi 530021, People’s Republic of ChinaTel +0086-771-5356534Fax +86 0771-5356534Email dangyiwu@126.comIntroduction: MIR22HG has a reported involvement in the tumorigenesis of a variety of cancers, including hepatocellular carcinoma (HCC). However, the exact molecular mechanism of MIR22HG in HCC has not been clarified.Methods: In the present study, we integrated data from in-house RT-qPCR, RNA-sequencing, microarray, and literature studies to conduct a comprehensive evaluation of the clinico-pathological and prognostic significance of MIR22HG in an extremely large group of HCC samples. We also explored the potential mechanism of MIR22HG in HCC by analyzing the alteration profiles of MIR22HG in HCC to predict transcription factors (TFs) that may interact with MIR22HG and to annotate the biological functions of genes co-expressed with MIR22HG. MIR22HG expression was also compared in HCC nude mice xenografts before and after a treatment with nitidine chloride.Results: We found that MIR22HG was downregulated in HCC and that this downregulation correlated with the malignant phenotype of HCC. Comprehensive analysis of the prognostic impact of MIR22HG in HCC revealed a beneficial effect of MIR22HG on the survival outcome of HCC patients. Seven cases of MIR22HG deep deletion occurred in 360 of the cancer genome atlas (TCGA) provisional HCC samples. A total of 22 MIR22HG-TF-mRNA triplets in HCC were predicted by the lncRNAmap. Co-expressed genes of MIR22HG, identified by weighted correlation network analysis (WGCNA), mainly participated in the pathways involving osteoclast differentiation, chemokine signaling pathways, and hematopoietic cell lineage. In vivo experiments demonstrated that nitidine chloride could stimulate MIR22HG expression in HCC xenografts.Conclusion: In summary, MIR22HG may play a tumor-suppressive role in HCC by coordinating with predicted TFs and co-expressed genes, such as NLRP3, CSF1R, SIGLEC10, and ZEB2, or by being controlled by nitidine chloride.Keywords: MIR22HG, hepatocellular carcinoma, RT-qPCR, transcription factor, co-expressed genes, nitidine chloride