Theranostics 2018; 8(19):5213-5230. doi:10.7150/thno.28001

Research Paper

PIWI-interacting RNA-54265 is oncogenic and a potential therapeutic target in colorectal adenocarcinoma

Dongmei Mai1#, Peirong Ding2#, Liping Tan1#, Jialiang Zhang1, Zhizhong Pan2, Ruihong Bai1, Cong Li2, Mei Li3, Yifeng Zhou4, Wen Tan5, Zhixiang Zhou6, Yexiong Li7, Aiping Zhou8, Ying Ye1, Ling Pan1, Yanfen Zheng1, Jiachun Su1, Zhixiang Zuo1, Zexian Liu1, Qi Zhao1, Xiaoxing Li1, Xudong Huang1, Wei Li4, Siqi Wu4, Weihua Jia1, Shuangmei Zou9, Chen Wu5, Rui-hua Xu10✉, Jian Zheng1✉, Dongxin Lin1,5

1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China
2. Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China;
3. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China;
4. Department of Cancer Genetics, Medical College of Soochow University, Suzhou 215123, P. R. China;
5. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China;
6. Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China;
7. Department of Radiation Oncology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China;
8. Department of Medical Oncology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China;
9. Department of Pathology, National Cancer Center/ National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P. R. China;
10. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
#Dongmei Mai, Peirong Ding and Liping Tan contributed equally to this work.

Abstract

Although PIWI-interacting RNAs (piRNAs) have recently been linked to human diseases, their roles and functions in malignancies remain unclear. This study aimed to investigate the significance of some piRNAs in colorectal cancer (CRC).

Methods: We first analyzed the expression profile of piRNAs in CRC using the TCGA and GEO databases. The top 20 highly expressed piRNAs were selected and tested in our CRC tumor and non-tumor tissue samples. We then examined the relevance of the significantly differentially expressed piRNA to the CRC outcomes in 218 patients receiving postoperative chemotherapy and 317 patients receiving neoadjuvant chemotherapy. A series of biochemical and molecular biological assays were conducted to elucidate the functional mechanism of a piRNA of interest in CRC. Furthermore, experiments with mice xenografts were performed to evaluate the therapeutic effect of an inhibitor specific to the piRNA.

Results: We found that among the examined 20 piRNAs, only piRNA-54265 was overexpressed in CRC compared with non-tumor tissues and higher levels in tumor or in serum were significantly associated with poor survival in patients. Functional assays demonstrated that piRNA-54265 binds PIWIL2 protein and this is necessary for the formation of PIWIL2/STAT3/phosphorylated-SRC (p-SRC) complex, which activates STAT3 signaling and promotes proliferation, metastasis and chemoresistance of CRC cells. Treatment with a piRNA-54265 inhibitor significantly suppressed the growth and metastasis of implanted tumors in mice.

Conclusion: These results indicate that piRNA-54265 is an oncogenic RNA in CRC and thus might be a therapeutic target.

Keywords: piRNA, biomarker, STAT3, therapeutic target, colorectal cancer

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How to cite this article:
Mai D, Ding P, Tan L, Zhang J, Pan Z, Bai R, Li C, Li M, Zhou Y, Tan W, Zhou Z, Li Y, Zhou A, Ye Y, Pan L, Zheng Y, Su J, Zuo Z, Liu Z, Zhao Q, Li X, Huang X, Li W, Wu S, Jia W, Zou S, Wu C, Xu Rh, Zheng J, Lin D. PIWI-interacting RNA-54265 is oncogenic and a potential therapeutic target in colorectal adenocarcinoma. Theranostics 2018; 8(19):5213-5230. doi:10.7150/thno.28001. Available from http://www.thno.org/v08p5213.htm