Chang Yu-Hsun, Wu Kun-Chi, Wang Kai-Hung, Ding Dah-Ching
Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University Hualien, Taiwan.
Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University Hualien, Taiwan.
Am J Cancer Res. 2023 Aug 15;13(8):3324-3341. eCollection 2023.
This study explored the role of leucine-rich repeat neuronal 4 (LRRN4) in ovarian carcinogenesis using the p53- and Rb-defective human fallopian tube epithelial cell line FE25. We evaluated the expression of LRRN4 in FE25 cells with and without LRRN4 knockdown by short hairpin RNA (shRNA) and studied its effects on cell proliferation, cell cycle, migration, invasion, chemotherapeutic sensitivity, apoptosis, and xenograft formation. The results showed that FE25 shRNA-LRRN4 cells exhibited more aggressive malignant behaviors than FE25 cells, including faster proliferation and increased cell distribution in the G2/M phase, Akt pathway activation, cell migration, and cell invasion, as well as decreased sensitivity to chemotherapeutic drugs. FE25 shRNA-LRRN4 cells exhibited reduced levels of apoptosis and decreased expression of cleaved caspase 3, 7, 8, and 9, indicating reduced apoptotic activity. Additionally, FE25 shRNA-LRRN4 cells showed decreased LRRN4 and CK7 expression and increased WT1 expression, suggesting a potential role for LRRN4 in ovarian carcinogenesis. FE25 shRNA-LRRN4 generated a xenograft in mice with increased levels of and expression compared to their levels in cells. Overall, this study suggests that LRRN4 may play a role in ovarian carcinogenesis by promoting aggressive malignant behavior in FE25 cells through the activation of the Akt pathway. These findings provide insights into the potential molecular mechanisms underlying ovarian cancer and may have implications for the development of new therapeutic targets for this disease.
本研究利用p53和Rb缺陷的人输卵管上皮细胞系FE25，探讨富含亮氨酸重复序列神经元4（LRRN4）在卵巢癌发生中的作用。我们通过短发夹RNA（shRNA）评估了LRRN4敲低和未敲低的FE25细胞中LRRN4的表达，并研究了其对细胞增殖、细胞周期、迁移、侵袭、化疗敏感性、凋亡和异种移植形成的影响。结果显示，FE25 shRNA-LRRN4细胞比FE25细胞表现出更具侵袭性的恶性行为，包括更快的增殖、G2/M期细胞分布增加、Akt通路激活、细胞迁移和细胞侵袭，以及对化疗药物的敏感性降低。FE25 shRNA-LRRN4细胞凋亡水平降低，裂解的半胱天冬酶3、7、8和9的表达减少，表明凋亡活性降低。此外，FE25 shRNA-LRRN4细胞显示LRRN4和CK7表达降低，WT1表达增加，提示LRRN4在卵巢癌发生中可能发挥作用。与细胞中的水平相比，FE25 shRNA-LRRN4在小鼠中产生的异种移植瘤中 和 表达水平增加。总体而言，本研究表明，LRRN4可能通过激活Akt通路促进FE25细胞的侵袭性恶性行为，从而在卵巢癌发生中发挥作用。这些发现为卵巢癌潜在的分子机制提供了见解，可能对该疾病新治疗靶点的开发具有启示意义。
