Abstract
The leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) is considered to be a stem cell marker in many normal tissues and promotes tissue development, regeneration, and repair. LGR6 is also related to the initiation and progression of some malignant tumors. However, the role of LGR6 in cervical cancer has not been reported. Here, immunohistochemistry and western blotting showed that LGR6 was significantly upregulated in cervical cancer, compared with the normal cervix. By analyzing The Cancer Genome Atlas database, LGR6 was found to be correlated with a poor prognosis of cervical cancer. Then, a small population of LGR6high cells isolated by using the fluorescence-activated cell sorting exhibited enhanced properties of cancer stem cells including self-renewal, differentiation, and tumorigenicity. Moreover, RNA sequencing revealed that LGR6 was correlated with the Wnt signaling pathway and TOP/FOP, reverse transcription-PCR, and western blotting further proved that LGR6 could activate the Wnt/β-catenin signaling pathway. Interestingly, LGR6 upregulated the expression of TCF7L2 by activating the Wnt/β-catenin pathway. Then, TCF7L2 combining with β-catenin in the nucleus enhanced LGR6 transcription by binding the promoter of LGR6, which further activated the Wnt signaling to form a positive feedback loop. Thus, our study demonstrated that LGR6 activated a novel β-catenin/TCF7L2/LGR6-positive feedback loop in LGR6high cervical cancer stem cells (CSCs), which provided a new therapeutic strategy for targeting cervical CSCs to improve the prognosis of cervical cancer patients.
Highlights
Cervical cancer is the fourth in female cancer with ~569,847 cases and 311,365 deaths in 2018 worldwide [1]
leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) is elevated in cervical cancer and is associated with a poor prognosis To explore the role of LGR6 in cervical cancer, the subcellular location and expression of LGR6 in 31 cervical cancer and 23 normal cervix (NC) samples were detected by immunohistochemistry (IHC)
We asserted that a small fraction of LGR6high cervical cancer cells was strongly enriched for cervical Cancer stem cells (CSCs) and LGR6 activated the Wnt signaling in these LGR6high cells
Summary
Cervical cancer is the fourth in female cancer with ~569,847 cases and 311,365 deaths in 2018 worldwide [1]. The prognosis of some women with recurrent or metastatic cervical cancer remains poor [7]. Cancer stem cells (CSCs), exhibiting stem cell characteristics including self-renewal, differentiation [8], and tumorigenic properties, play crucial roles in tumor initiation, metastasis, and recurrence [9]. Drugs targeting signaling pathways regulating CSCs could improve cancer patient prognosis [10, 11]. It has been found that some genes could play a role in maintaining CSC properties in cervical cancer. Our previous studies have indicated that ALDH might be a marker of cervical CSCs [15] and some stem cell-associated genes such as SOX2 [16], OCT4 [17], and LGR5 [18, 19] are closely associated with tumorigenesis in cervical cancer. It has been reported that Erlotinib can overcome paclitaxel-resistant cervical CSCs [20] and zoledronic acid attenuates the stemness phenotype in cervical cancer by suppressing phosphorylated Erk1/2 and Akt [21]
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