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// Xinying Xue 1, 2 , Yuxia Liu 3 , Yong Wang 1 , Mingming Meng 4 , Kaifei Wang 2 , Xuefeng Zang 5 , Sheng Zhao 6 , Xiaohua Sun 7 , Lei Cui 8 , Lei Pan 1 , Sanhong Liu 9 1 Department of Special Medical Treatment-Respiratory Disease, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 2 Department of Respiratory Diseases of Chinese PLA General Hospital, Beijing, China 3 Department of Research, Peking Union Medical Collage Hospital, Beijing, China 4 Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 5 Department of Intensive Care Unit, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 6 Department of Cardiology, Peking University Ninth School of Clinical Medicine, Beijing Shijitan Hospital, Beijing, China 7 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China 8 Department of Central Laboratory, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 9 Shanghai Institute of Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China Correspondence to: Lei Pan, email: leipan2010@163.com Sanhong Liu, email: liush@shanghaitech.edu.cn Lei Cui, email: cuileite@aliyun.com Keywords: non-small cell lung carcinoma, miR-21, miR-155, SOCS1, SOCS6 Received: July 11, 2016 Accepted: October 25, 2016 Published: November 02, 2016 ABSTRACT Lung cancer remains the leading cause of cancer-associated death worldwide. MiR-21 and miR-155 are the most amplified miRNAs in non-small cell lung carcinoma (NSCLC), and are critical promoters of NSCLC progression. However, it remains unclear how miR-21 and miR-155 induce cancer progression, and whether these miRNAs share common targets, such as tumor suppressor genes required to prevent NSCLC. Here we report that miR-21 and miR-155 levels are elevated in NSCLC and are proportional to the progression of the disease. In addition, miR-21 and miR-155 share nearly 30% of their predicted target genes, including SOCS1 , SOCS6 , and PTEN , three tumor suppressor genes often silenced in NSCLC. Consequently, antagonizing miR-21, miR-155 or both potently inhibited tumor progression in xenografted animal models of NSCLC. Treatment with miR-21 and miR-155 inhibitors in combination was always more effective against NSCLC than treatment with a single inhibitor. Furthermore, levels of miR-21 and miR-155 expression correlated inversely with overall and disease-free survival of NSCLC patients. Our findings reveal that miR-21 and miR-155 promote the development of NSCLC, in part by downregulating SOCS1 , SOCS6 , and PTEN . Combined inhibition of miR-21 and miR-155 could improve the treatment of NSCLC.

// Ran Chen 1, * , Lunshan Wang 2, * , Sanhong Liu 3 , Xi Chen 1 , Yiming Hu 1 , Hanshao Liu 1 , Haohao Zhang 1 , Yuhang Jiang 1 , Qi Wang 1 , Deji Ye 1 , Lingling Li 1 , Dandan Liu 1 , Xiaorong Pan 4 , Lixin Wei 4 , Xuemei Li 5 and Xiaoren Zhang 1 1 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China 2 Clinical Laboratory Department, The Chinese People’s Liberation Army 105th Hospital, Hefei 230001, China 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China 4 Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China 5 Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100723, China * These authors have contributed equally to this work Correspondence to: Xiaoren Zhang, email: xrzhang@sibs.ac.cn Xuemei Li, email: lixmpumch@126.com Keywords: Bcl-3, renal fibrosis, chronic kidney disease, unilateral ureteral obstruction, biomarker Received: June 27, 2017 Accepted: August 31, 2017 Published: October 09, 2017 ABSTRACT Progressive renal fibrosis in chronic kidney disease (CKD) greatly contributes to end-stage renal failure and is associated with high mortality. The identification of renal fibrosis biomarkers for the diagnosis and the monitoring of disease progression in CKD is urgently needed. Whole-transcriptomic analysis of renal tissues in a unilateral ureteral obstruction (UUO) mouse model revealed that the mRNA level of Bcl-3, an atypical member of the IκB family, was induced 6.3-fold 2 days after UUO. Compared with renal tissues in sham-operated mice, increases in Bcl-3 mRNA and protein in the renal tissues in the UUO model were accompanied with increases in other markers of renal fibrosis, including human epididymis protein 4 (HE4), a recently identified biomarker of renal fibrosis. Immunohistochemical analysis revealed that both Bcl-3 and HE4 were located in the plasma of renal tubule cells. Serum protein levels of Bcl-3 and HE4 rose with the development of renal fibrosis in UUO mouse model. We found that the serum protein levels of both HE4 and Bcl-3 were elevated in CKD patients compared with healthy controls. Moreover, a significant positive correlation between Bcl-3 and HE4 (r = 0.939, p < 0.0001) was observed in CKD patients. These data suggest that Bcl-3 can serve as a novel valuable biomarker of renal fibrosis in CKD.

miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.