Abstract
Current evidence suggests that oral cancer stem cells (OCSCs) possess high tumorigenic and metastatic properties as well as chemo- and radioresistance. In this study, we demonstrated that andrographolide, the main bioactive component in the medicinal plant Andrographis, significantly reduced oncogenicity and restored radio-sensitivity of ALDH1+CD44+ OCSCs. Mechanistic studies showed that andrographolide treatment increased the expression of microRNA-218 (miR-218), leading to the downregulation of Bmi1. We showed that knockdown of miR-218 in ALDH1−CD44− non-OCSCs enhanced cancer stemness, while silencing of Bmi1 significantly counteracted it. Furthermore, we found tumor growth was reduced in mice bearing xenograft tumors after andrographolide treatment via activation of miR-218/Bmi1 axis. Together, these data demonstrated that the inhibition of tumor aggressiveness in OCSCs by andrographolide was mediated through the upregulation of miR-218, thereby reducing Bmi1 expression. These findings suggest that andrographolide may be a valuable natural compound for anti-CSCs treatment of OSCC.
Highlights
Oral squamous cell carcinomas (OSCC) ranks as the sixth most common cancer with high incidence and represents a significant contributor to burden of cancer globally [1]
We showed that knockdown of miR-218 in ALDH1−CD44− non-oral cancer stem cells (OCSCs) enhanced cancer stemness, while silencing of Bmi1 significantly counteracted it
ALDH1+CD44+ OCSCs were isolated from patientderived cell lines and used to study the cancer stem cells (CSCs) properties, since ALDH1 and CD44 have been recognized as markers to distinguish malignant from premalignant cells as well as identify the putative OCSCs [33, 34]
Summary
Oral squamous cell carcinomas (OSCC) ranks as the sixth most common cancer with high incidence and represents a significant contributor to burden of cancer globally [1]. Treatments including extensive surgery, radiotherapy, chemotherapy or concurrent chemo/ radiation are not effective for patients with advanced OSCC due to tumor recurrence, metastasis, or poor response to chemo/ radiotherapy [1]. It has been indicated that cervical lymph node metastasis is the major cause of death in OSCC patients [1]. It is necessary to identify effective therapies for these patients and understand the molecular mechanisms underlying lymph node metastasis. Given that cancer stem cells (CSCs) have been considered to be responsible for metastasis and resistance to chemo/radiotherapy in OSCC [2,3,4], CSCs-targeted therapy may be a useful strategy against OSCC. Our previous study has shown that OSCC-CSCs were highly tumorigenic, metastatic, resistant to radio/chemotherapy and had increased expression of epithelial-mesenchymal transition (EMT) markers [3]. Other recent reports revealed that CD44 [5], CD133 [6], aldehyde dehydrogenase (ALDH) [7], membrane GRP78 [8], side population [9] and c-Met [10] could be used to detect CSCs from OSCC as well
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