Cyclooxygenase‑2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma

Abstract

Cyclooxygenase-2 (COX-2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is associated with the progression in various types of cancer, and its expression has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX-2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX-2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX-2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resection with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX-2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX-2 expression with stemness property, the expression levels of CSC-associated genes after exposure to celecoxib were assessed by reverse transcription-quantitative PCR. A sphere formation assay was also performed using ultra-low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX-2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX-2 inhibition led to downregulation of CSC-associated gene expression and sphere formation. The present findings suggested that COX-2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX-2 may enhance chemo-sensitivity in HNSCC. Therefore, COX-2 may be an attractive target for the treatment of HNSCC.

Increased response to TPF chemotherapy promotes immune escape in hypopharyngeal squamous cell carcinoma

“…Many studies have confirmed single genetic markers associated with chemotherapy sensitivity in HPSCC. For instance, COX-2 expression has been found to be associated with chemoresistance through the cancer stemness property (Saito et al, 2021). The ctDNA might play a significant role in DDP resistance in HPSCC by amplifying related functional genes (Lin et al, 2022).…”

Advancement in Cancer Stem Cell Biology and Precision Medicine—Review Article Head and Neck Cancer Stem Cell Plasticity and the Tumor Microenvironment

“…A study investigating the effects of COX-2 inhibition in hypopharyngeal cancer resulted in deceased expression of genes associated with CSCs and reduced sphere formation. Tumor viability was also decreased and these results were improved by the addition of docetaxel ( Saito et al, 2021 ). Dong et al demonstrated that inhibition of Bromo- and Extra-Terminal domain (BET) results in an unanticipated impairment of super enhancers and reduced stemness in HNC ( Dong et al, 2021 ).…”

“…Proponents of the cancer stem cell model argue that because CSCs are thought to be relatively resistant to radiation and chemotherapy; they evade initial treatment modalities and subsequently are able to recreate the heterogeneous tumor. As such it is this small subset of cells that needs to be targeted in order to eradicate the tumor ( Bao et al, 2006 ; Dick 2008 ; Al-Assar et al, 2009 ; Mroz et al, 2013 ; Dionne et al, 2015 ; Subramanian et al, 2017 ; Zonga et al, 2018 ; Hu et al, 2019 ; Shibata and Hoque 2019 ; Keysar et al, 2020 ; Saito et al, 2021 ). More recently there has been an evolution in this model that suggests an inherent plasticity to CSCs that is mediated through the TME, arguing against the unidirectionality of the CSCs models ( Chaffer et al, 2013 ; Sancho et al, 2015 ; Shimokawa et al, 2017 ; Ahmed et al, 2018 ; Yao et al, 2019 ; Heise and Sommer 2021 ).…”

Delta-5-desaturase: A novel therapeutic target for cancer management

“… Molecules Cancer type Clinical outcomes Prognostic/ predictive utility Ref. D5D Non-small-cell lung cancer Higher expression in normal bronchial mucosa than tumor tissues Negatively associates with tumor size and histological grade Lower expression associates with shorter overall survival and disease-free survival Protective [27] D5D Esophageal squamous cell carcinoma Associates with better disease-free survival and overall survival Protective [28] D5D Bladder cancer Positively associates with tumor grade Enhances the proliferation Poor prognosis [13] D5D Laryngeal squamous cell carcinoma High expression and bioactivity in tumor tissues Undetermined [14] D5D rs174549 Oral cancer Correlates to a decreased risk of oral cancer Protective [37] D5D rs174548 Lung cancer Smoking-independent Particularly associates with lung cancer in women Undetermined [34] COX-2 Hypopharyngeal carcinoma Associates with chemoresistant Undetermined [38] COX-2 Colorectal cancer Relates to susceptibility to cancer in Caucasians Increased risk [39] COX-2 Osteosarcoma Higher expression in osteosarcoma than benign osteochondroma Associates with tumor grade, clinical stage, and metastasis Poor prognosis [40] COX-2 Breast cancer High expression associates with poor overall survival Poor prognosis …”