Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells, contribute to tumorigenesis, resistance to chemoradiotherapy and recurrence in human cancers, suggesting targeting CSCs may represent a potential therapeutic strategy. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) has recently been found to be a bona fide marker of colorectal CSCs. Our previous study showed that LGR5 functions as a tumor promoter in cervical cancer by activating the Wnt/β-catenin pathway. However, very little is known about the function or contribution of LGR5 to cervical CSCs. Here, we have modulated the expression of LGR5 using an overexpression vector or short hairpin RNA in cervical cancer cell lines. We demonstrated that elevated LGR5 expression in cervical cancer cells increased tumorsphere-forming efficiency; conferred chemoresistance to cisplatin treatment; augmented cell migration, invasion and clonogenicity; and elevated the levels of stem cell-related transcription factors in vitro. Furthermore, modulated LGR5+ cells, unlike LGR5− cells, were highly tumorigenic in vivo. In addition, the modulated LGR5+ cells could give rise to both LGR5+ and LGR5− cells in vitro and in vivo, thereby establishing a cellular hierarchy. Finally, we found that the increased tumorsphere-forming efficiency induced by LGR5 could be regulated through the inhibition or activation of the Wnt/β-catenin pathway in cervical cancer cells. Taken together, these results indicate that LGR5 has a vital oncogenic role by promoting cervical CSC traits and may represent a potential clinical target.
Highlights
Cervical cancer is the third most common type of malignant tumor and the fourth leading cause of cancer death among women worldwide.[1,2] Cervical cancer development begins with the infection of the cervical epithelium by high-risk human papillomaviruses.[3]
A number of studies have found that several stem cell-related genes are closely associated with tumorigenesis, and it has been demonstrated that SOX2,7 NANOG,[8] KLF4,9 OCT410 and LGR511 have critical roles in cervical carcinogenesis
As a cancer stem cells (CSCs) marker, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) has been shown to be progressively expressed in cervical carcinogenesis and to promote cancer cell proliferation and tumor formation
Summary
Cervical cancer is the third most common type of malignant tumor and the fourth leading cause of cancer death among women worldwide.[1,2] Cervical cancer development begins with the infection of the cervical epithelium by high-risk human papillomaviruses.[3]. Many studies have revealed that LGR5 is overexpressed in various types of tumors, including colorectal cancer,[15] ovarian tumors,[16] hepatocellular carcinoma,[17] basal cell carcinoma[18] and esophageal adenocarcinoma.[19] In addition, LGR5 has been recognized as a CSC marker for colorectal cancers.[20] Our previous study showed that LGR5 was progressively expressed in cervical carcinogenesis and promoted the proliferation of cervical cancer cells as well as tumor formation by potentiating the Wnt/β-catenin pathway.[11] we hypothesized that LGR5 might contribute to cervical carcinogenesis, recurrence and metastasis by maintaining the stemness of cervical CSCs. In this study, we used standard functional assays and fluorescence activated cell sorting (FACS) to analyze the properties of cervical CSCs with different levels of LGR5 expression.
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