Abstract
Numerous findings have demonstrated that long noncoding RNA (lncRNA) dysregulation plays a key role in many human neoplasms, including tongue squamous cell carcinoma (TSCC), yet the potential mechanisms of lncRNAs in chemo-resistance remain elusive. Our research showed that the lncRNA KCNQ1OT1 was upregulated in chemo-insensitive TSCC tissues compared with chemo-sensitive TSCC specimens. Meanwhile, high KCNQ1OT1 expression was closely correlated with poor prognosis. Furthermore, KCNQ1OT1 promoted TSCC proliferation and conferred TSCC resistance to cisplatin-induced apoptosis in vitro and in vivo. Using online database analysis, we predicted that the lncRNA KCNQ1OT1 facilitates tumor growth and chemo-resistance by acting as a competing endogenous RNA (ceRNA) to modulate the expression of miR-211-5p. And miR-211-5p upregulation significantly impaired TSCC proliferation and resumed TSCC chemo-sensitivity, which is contrary to the function of lncRNA KCNQ1OT1. Luciferase experiments confirmed that miR-211-5p harbor binding sites for the 3′-UTRof Ezrin mRNA, and Ezrin/Fak/Src signaling was activated in cisplatin-resistant TSCC cells. Finally, miR-211-5p inhibition in sh-KCNQ1OT1-expressing TSCC cells rescued the suppressed cell proliferation and cisplatin resistance induced by KCNQ1OT1 knockdown. In summary, our study has elucidated the role of the oncogenic lncRNA KCNQ1OT1 in TSCC growth and chemo-resistance, which may serve as a new target for TSCC therapy.
Highlights
Tongue squamous cell carcinoma (TSCC) is one of the most frequently diagnosed malignancies in the oral cavity, and it is associated with a poor prognosis due to its high rate of regional recurrence and lymphoid metastasis[1]
These results indicated that the long noncoding RNA (lncRNA) KCNQ1OT1 may be involved in the occurrence and development of chemo-resistance, and it may serve as a potential marker to predict chemoresponsiveness and prognosis in TSCC patients
The dysregulation of lncRNAs has been reported to be involved in numerous biological processes, such as cell proliferation, cell cycle progression, cell invasion, cell migration, and chemoresistance, in various neoplasms, including breast cancer, gastric cancer, and bladder cancer[21,22,23]
Summary
Tongue squamous cell carcinoma (TSCC) is one of the most frequently diagnosed malignancies in the oral cavity, and it is associated with a poor prognosis due to its high rate of regional recurrence and lymphoid metastasis[1]. The underlying mechanisms resulting in cisplatin resistance in tongue cancer cells remain poorly understood. Many studies have proven that the dysregulation of noncoding RNAs, including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), contribute to chemoresistance. LncRNAs are RNA transcripts that are greater than 200 nucleotides but lack protein coding potential, and in multiple tumors, they regulate the expression of genes related to aberrant proliferation and Official journal of the Cell Death Differentiation Association. The lncRNA HOXDAS1 is significantly overexpressed in tongue cancer and promotes proliferation and chemo-resistance by recruiting WDR56. A previous study indicated that the lncRNA MRUL mediated chemo-resistance in gastric cancer cells via regulating ABCB1 expression[7]. Numerous studies reiterate the importance of lncRNAs in tumor chemoresistance, the molecular mechanisms of TSCC chemo-resistance are not well understood
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