謝嘉興^a、蕭璦莉^c、吳昭良^b

衛生福利部 台南醫院 泌尿科^a, 國立成功大學醫學院 生化所^b，國立成功大學醫學院 微免所^c

Gia-Shing Shieh^a, Ai-Li Shiau^c, and Chao-Liang Wu^b

^a Department of Urology, Tainan Hospital, Ministry of Health and Welfare, Taiwan,

^b Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan,

^c Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

 

Purpose: Prothymosin-α (ProT) involved in cell proliferation, apoptosis, oxidative stress, and immunomodulation. Long non-coding RNAs (lncRNAs), were involved in the epigenetic regulation of coding genes in numerous human cancers. Several studies have shown that the lncRNA HOTAIR is involved in various cancers. The transcriptional upregulation of HOTAIR, induced by NF-κB, contributed to chemotherapy resistance and IL-6 expression in ovarian cancers. IL-6 was a major cytokine to induce cancer cachexia. We recently reported that ProT contributed to the pathogenesis of emphysema by increasing acetylation of histones and NF-κB. In this study, we will evaluate whether ProT activates HOTAIR upregulation via NF-κB signaling. Furthermore, we will study whether HOTAIR induces cachexia in bladder cancer models.

Methods: Human and murine bladder cancer cells were used in the study. ELISA studies were performed for cytokine assays. Real-time RT-PCR assays were performed for ProT and HOTAIR expressions. The knockdown expression of HOTAIR was induced via CRISPRi system. MBT-2 bladder tumors, treated with cisplatin, were created for cancer cachexia models. Group differences were determined by Student t test. All statistical tests were two-sided.

Result: The expressions of ProT and HOTAIR in human bladder cancer tissues were higher than those in their normal counterparts. The ProT levels were positively correlated with HOTAIR activities in human bladder cancer tissues. In vitro studies showed that ProT induced HOTAIR expressions via NF-κB signaling pathway. In bladder cancer cells, downregulation of HOTAIR activities suppressed inflammation cytokine expressions, such as IL-1β, IL-6 and TNF-α. Cisplatin activated overexpressions of ProT and HOTAIR in in vitro studies and induced cancer cachexia in MBT-2-bearing mice. Knockdown HOTAIR expressions retarded tumor growth, reduced cancer cachexia and inhibited inflammation cytokine activities.

Conclusion: Our results suggested that ProT-NF-κB-HOTAIR-cytokine axis played a pivotal role in cancer cachexia models. The inhibition of ProT-HOTAIR signaling provided the therapeutic potential for cancer cachexia.