MicroRNA-18a targeting of the STK4/MST1 tumour suppressor is necessary for transformation in HPV positive cervical cancer

Abstract

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a subset of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.

E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

“…HPV E5 functions as an ion channel, induces EGFR signalling and promotes resistance to anti-PD-L1 immunotherapy [3][4][5][6]. E6 and E7 are the primary drivers of viral oncogenesis; in addition to their well-characterised inactivation of the p53 and pRb tumour suppressors [7,8], they regulate a multitude of signalling pathways that contribute to transformation [9][10][11][12][13][14][15].…”

lncRNA GAS5 enhances tumor stem cell-like medicated sensitivity of paclitaxel and inhibits epithelial-to-mesenchymal transition by targeting miR-18a-5p/STK4 pathway in prostate cancer

“…Moreover, the experiments further veri ed the changes of miR-18a-5p expression level in PR PCA cell lines directly affected one of its downstream targets in expression, STK4, also known as STK4 (mammalian sterile 20-like kinase 1) [55]. It has been identi ed as a tumor suppressor in multiple cancers [39,56], as the same result as in PCA. In addition, the interaction effect between miR-18a-5p and STK4 suggested synergy between miR-18a-5p inhibitor and STK4 caused enhanced paclitaxel sensitivity by reduced the IC50.…”

Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy

“…miR-18a belonging to the miR-17-92 cluster has been found to either promote or inhibit tumorigenesis, suggesting its dual function in cancer progression. On the one hand, miR-18a-5p was demonstrated to play an oncogenic role by regulating downstream targets and promoting cancer progression in various cancer types such as lung cancer (Liang et al, 2017), cervical cancer (Morgan et al, 2020), prostate cancer (Hsu et al, 2014) and gastric cancer (Wu et al, 2013;Tsujiura et al, 2015). On the other hand, miR-18a-5p was found to inhibit malignant progression of breast cancer (Godfrey et al, 2013;Zhang N. et al, 2019), colorectal cancer (Vega et al, 2013) and pancreatic cancer (Li et al, 2017).…”