Knockdown of PLAC1 inhibits BCa growth and migration through upregulation of FOXO3a

Placenta-specific protein 1 (PLAC1) is considered to play a pivotal role in cancer progression. Here, we investigated the role of PLAC1 in the growth and motility of bladder cancer (BCa) cells. Database analysis and Immunoblot assays were conducted to determine PLAC1 expression in BCa tissues and its correlation with patient prognosis. Furthermore, wound healing, transwell and tube formation assays were performed to evaluate cell motility and angiogenic potential, and the underlying mechanism via which PLAC1 knockdown inhibits BCa progression in vitro was investigated. The data revealed that PLAC1 was obviously overexpressed in BCa tissues and was associated with poor patient prognoses. Additionally, silencing PLAC1 led to reduced viability, migratory capacity, invasion potential and angiogenesis of BCa cells, including T24 and UMUC3 cells. Further investigation showed that PLAC1 knockdown modulated the phosphoinositide 3-kinase/protein kinase B/forkhead box O3a (PI3K/Akt/FOXO3a) axis by enhancing the phosphorylation of FOXO3a while suppressing the phosphorylation of PI3K as well as Akt. Moreover, we demonstrated that the inhibition of BCa progression by PLAC1 knockdown was primarily mediated through the targeting of FOXO3a. In summary, these findings confirmed the potential of PLAC1 as a promising target for suppressing BCa growth by elevating FOXO3a levels and modulating the PI3K/Akt/FOXO3a signaling axis.

Angiogenesis; PLAC1; BCa; FOXO3a; PI3K/Akt pathway

[1] Huang J, Zhou W, Hao C, He Q, Tu X. The feedback loop of METTL14 and USP38 regulates cell migration, invasion and EMT as well as metastasis in BCa. PLOS Genetics. 2022; 18: e1010366.

[2] Farling KB. Bladder cancer: risk factors, diagnosis, and management. Nurse Practitioner. 2017; 42: 26–33.

[3] Tan S, Kang Y, Li H, He HQ, Zheng L, Wu SQ, et al. circST6GALNAC6 suppresses BCa metastasis by sponging miR-200a-3p to modulate the STMN1/EMT axis. Cell Death & Disease. 2021; 12: 168.

[4] Bi J, Liu H, Dong W, Xie W, He Q, Cai Z, et al. Circular RNA circ-ZKSCAN1 inhibits BCa progression through miR-1178-3p/p21 axis and acts as a prognostic factor of recurrence. Molecular Cancer. 2019; 18: 133.

[5] Yi L, Wang H, Li W, Ye K, Xiong W, Yu H, et al. The FOXM1/RNF26/p57 axis regulates the cell cycle to promote the aggressiveness of BCa. Cell Death & Disease. 2021; 12: 944.

[6] Li Y, Chu J, Li J, Feng W, Yang F, Wang Y, et al. Cancer/testis antigen-Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway. Molecular Oncology. 2018; 12: 1233–1248.

[7] Liu D, Shi K, Fu M, Chen F. Placenta-specific protein 1 promotes cell proliferation via the AKT/GSK-3beta/cyclin D1 signaling pathway in gastric cancer. IUBMB Life. 2021; 73: 1131–1141.

[8] Wu Y, Lin X, Di X, Chen Y, Zhao H, Wang X. Oncogenic function of Plac1 on the proliferation and metastasis in hepatocellular carcinoma cells. Oncology Reports. 2017; 37: 465–473.

[9] Ma J, Li L, Du J, Pan C, Zhang C, Chen Y. Placenta-specific protein 1 enhances liver metastatic potential and is associated with the PI3K/AKT/NF-κB signaling pathway in colorectal cancer. European Journal of Cancer Prevention. 2021; 30: 220–231.

[10] Yan F, Liao R, Silva M, Li S, Jiang Y, Peng T, et al. Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway. Journal of Cellular and Molecular Medicine. 2020; 24: 6208–6219.

[11] Calissi G, Lam EW, Link W. Therapeutic strategies targeting FOXO transcription factors. Nature Reviews Drug Discovery. 2021; 20: 21–38.

[12] Jiramongkol Y, Lam EW. FOXO transcription factor family in cancer and metastasis. Cancer and Metastasis Reviews. 2020; 39: 681–709.

[13] Zhang N, Hua X, Tu H, Li J, Zhang Z, Max C. Isorhapontigenin (ISO) inhibits EMT through FOXO3A/METTL14/VIMENTIN pathway in BCa cells. Cancer Letters. 2021; 520: 400–408.

[14] Chen R, Sheng C, Ma R, Zhang L, Yang L, Chen Y. PLAC1 is an independent predictor of poor survival, and promotes cell proliferation and invasion in cervical cancer. Molecular Medicine Reports. 2021; 24: 800.

[15] Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiological Reviews. 2011; 91: 1071–1121.

[16] Teoh JY, Kamat AM, Black PC, Grivas P, Shariat SF, Babjuk M. Recurrence mechanisms of non-muscle-invasive BCa—a clinical perspective. Nature Reviews Urology. 2022; 19: 280–294.

[17] Fant M, Farina A, Nagaraja R, Schlessinger D. PLAC1 (Placenta-specific 1): a novel, X-linked gene with roles in reproductive and cancer biology. Prenatal Diagnosis. 2010; 30: 497–502.

[18] An T, Deng L, Wang Y, Yang Z, Chai C, Ouyang J, et al. The prognostic impacts of PABPC1 expression on gastric cancer patients. Future Oncology. 2021; 17: 4471–4479.

[19] Lin C, Qian P, Zhang Y, Liu Z, Dai K, Sun D. Plac1 promotes nasopharyngeal carcinoma cells proliferation, migration and invasion via Furin/NICD/PTEN pathway. Tissue and Cell. 2021; 69: 101480.

[20] Yang L, Zha TQ, He X, Chen L, Zhu Q, Wu WB, et al. Placenta-specific protein 1 promotes cell proliferation and invasion in non-small cell lung cancer. Oncology Reports. 2018; 39: 53–60.

[21] Tan J, Xiang Y, Xiong Y, Zhang Y, Qiao B, Zhang H. Crebanine induces ROS-dependent apoptosis in human hepatocellular carcinoma cells via the AKT/FoxO3a signaling pathway. Frontiers in Pharmacology. 2023; 14: 1069093.

[22] Habrowska-Gorczynska DE, Koziel MJ, Kowalska K, Piastowska-Ciesielska AW. FOXO3a and its regulators in prostate cancer. International Journal of Molecular Sciences. 2021; 22: 12530.

[23] Sohn HY, Kim SI, Park JY, Park SH, Koh YH, Kim J, et al. ApoE4 attenuates autophagy via FoxO3a repression in the brain. Scientific Reports. 2021; 11: 17604.

[24] Chen H, Xu L, Wang L. Expression of miR-182 and Foxo3a in patients with BCa correlate with prognosis. International Journal of Clinical and Experimental Pathology. 2019; 12: 4193–4203.