Ectopic overexpression of CD133 in HNSCC makes it resistant to commonly used chemotherapeutics

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. Resistance to cytotoxic chemotherapy is a major cause of mortality in patients with HNSCC. A small subset of cancer cells called cancer stem cells (CSCs) may be key contributors to drug resistance and tumor recurrence in HNSCC. The aim of this study was to determine whether CD133, which maintains properties of CSCs, promotes chemoresistance by arresting cell cycle transition and reducing apoptosis in HNSCC cells. CD133 overexpression was examined in KB cells, and colony forming and aldehyde dehydrogenase activity assays were performed. To investigate the role of CD133 in chemoresistance, cell death was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Diff-Quick, flow cytometry, and western blot of apoptosis-related protein expression in fluorouracil (5-FU)-or cisplatin-treated cells. In addition, microarray and related protein expression assessments were performed to investigate the mechanism of chemoresistance against 5-FU and cisplatin in KB cells. Moreover, chemoresistance against 5-FU or cisplatin in a KB-inoculated mouse model was analyzed by hematoxylin and eosin staining, immunohistochemical study of CD133, and immunofluorescence of tumor tissue. In this study, we demonstrate that ectopic overexpression of CD133 significantly promotes properties of stemness in KB cell lines. Furthermore, CD133 promotes chemoresistance by arresting transition of the cell cycle and reducing apoptosis, which results in inhibition of tumor growth in 5-FU-or cisplatin-injected mouse tumor model. Taken together, our findings show that elevated levels of CD133 lead to HNSCC chemoresistance through increased stemness and cell cycle arrest.

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

“…Acquired chemoresistance represents a major challenge in the management of patients with OSCC [23,24]. The presence of CSCs was demonstrated in many cancer types, including OSCC, and they have been implicated in the development of treatment resistance [25,26]. Accumulating evidence EVs from OV+CDDP and OV-only regimens showed a markedly lower level of mammalian target of rapamycin (mTOR), phosphatidylinositol-3 kinase (PI3K), and β-catenin compared to those from the vehicle and CDDP-only groups.…”

“…Acquired chemoresistance represents a major challenge in the management of patients with OSCC [23,24]. The presence of CSCs was demonstrated in many cancer types, including OSCC, and they have been implicated in the development of treatment resistance [25,26]. Accumulating evidence indicates that CSCs are endowed with an enhanced ability to self-renew, efflux chemotherapeutic agents, and increase the epithelial-to-mesenchymal transition (EMT), as well as facilitate the production of a broad spectrum of oncogenic factors that constitutively remodel the TME which favors cancer progression [27,28].…”

CD133 as a regulator of cancer metastasis through the cancer stem cells

“…In addition to cancer initiation, development, and metastasis, CD133 also enhances therapeutic resistance including chemo drugs and radiation. Overexpression of CD133 in a head and neck squamous cell carcinoma (HNSCC) cell line rendered the cells insensitive to 5-FU-or cisplatin-induced cell death (Lee et al, 2017). Furthermore, the CD133 + HNSCCs were arrested at the G0/G1 phase of the cell cycle in response to 5-FU and cisplatin treatment.…”

Immunohistochemical expression of CD44 in oral squamous cell carcinoma in relation to histomorphological parameters and clinicopathological factors

“…In addition, CD44 expression has been linked to EMT . Whereas, in several malignancies, a correlation between CD44 expression and poor survival has been shown, the impact of CD44 expression on the prognosis of OSCC remains unclear, with contradictory results concerning prognostic value …”