1. NHC Key Laboratory of Carcinogenesis of Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine; School of basic Medical Science, Central South University, Changsha, Hunan 410013, China.
2. The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, 410078, China.
3. Hunan Key Laboratory of Non-resolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, Central South University, Changsha, 410013, China.
4. The department of gynecology of Xiangya Hospital, Central South University, Changsha, Hunan, China.
5. Jiangxi University of Science and Technology, Ganzhou, 341000, China; State Key Laboratory of High Performance Complex Manufacturing, Central South University, Changsha, 410083, China.
*These authors contributed equally to this work.
Ovarian cancer (OC) is one of the malignant tumors that seriously threaten women's health, with the highest mortality rate in gynecological malignancies. The prognosis of patients with advanced OC is still poor, and the 5-year survival rate is only 20-30%. Therefore, how to improve the early diagnosis rate and therapeutic effect are urgent for patients with OC. In this research, we found that Lin28A can promote the expression of stem cell marker molecules CD133, CD44, OCT4 and Nanog. We later confirmed that Lin28A can enrich the mRNA of ras-related nuclear protein (RAN) and heat shock factor binding protein 1 (HSBP1) through RIP assay, and that Lin28A can regulate their protein expression. We also identified that RAN and HSBP1 are highly expressed in OC tissues, and that they are significantly positively correlated with the expression of Lin28A and negatively correlated with the survival prognosis of OC patients. After stable knockdown of RAN or HSBP1 in OC cells with high expression of Lin28A, the expression of the stem cell marker molecules such as OCT4, CD44 and Nanog are reduced. And after knocking down of RAN or HSBP1 in Lin28A highly expressed OC cells, the survival and invasion of OC cells and tumor size of OC xenograft in nude mice were markedly inhibited and apoptosis was increased. Our data also showed that knock down of RAN or HSBP1 can inhibit the invasion ability of OC cells by decreasing the expression of N-cadherin, Vimentin and promoting the expression of E-cadherin. Meanwhile, knockdown of RAN or HSBP1 induced cell apoptosis by inhibiting the expression of PARP. Our results indicated that Lin28A could regulate the biological behaviors in OC cells through RAN/HSBP1. These findings suggest that Lin28A/RAN/HSBP1 can be used as a marker for diagnosis and prognosis of OC patients, and RAN/HSBP1 may be a potential new target for gene therapy of OC.
Keywords: Lin28A, RAN, HSBP1, stemness, apoptosis, invasion