LINC00461 facilitates HNSCC development and reduces chemosensitivity by impairing miR-195-mediated inhibition of HOXA10

Abstract

Homeobox A10 (HOXA10) has been regarded to serve as an oncogene in head and neck squamous cell carcinoma (HNSCC). This study was intended to explore the interaction among the long intergenic noncoding RNA 00461 (LINC00461), microRNA (miR)-195, and HOXA10, and to investigate its role in epithelial-mesenchymal transition (EMT) and chemoresistance in HNSCC. The effects of LINC00461, miR-195, and HOXA10 on the EMT and chemoresistance of HNSCC cells were analyzed by comprehensive analysis of gain- and loss-of-function techniques. The intimate relationships among LINC00461, miR-195, and HOXA10 were investigated by several procedures such as RNA-binding protein immunoprecipitation, RNA pull-down, and dual-luciferase reporter assays. A xenotransplantation tumor model in nude mice was established for the assessment of the tumorigenic ability of the cells in vivo . Our findings indicated that LINC00461 was highly expressed in HNSCC and its overexpression induced EMT and precipitated the chemoresistance of HNSCC cells to cisplatin. The LINC00461 could bind to miR-195 while miR-195 targeted HOXA10 independently. Moreover, LINC00461 impaired miR-195-mediated inhibition of HOXA10 to induce EMT and increase the chemoresistance in HNSCC. Tumor weight and volume were reduced by lentivirus-mediated elevation of miR-195 by inhibition of HOXA10, which could be annulled by LINC00461 overexpression. LINC00461 downregulates the expression of miR-195 to subsequently upregulate the expression of HOXA10, thereby promoting EMT and enhancing chemoresistance in HNSCC.

Effects of MicroRNA‐195‐5p on Biological Behaviors and Radiosensitivity of Lung Adenocarcinoma Cells via Targeting HOXA10

“…Our bioinformatics results also showed that miR-195-5p might be a tumor suppressor gene in lung cancer [ 13 ], and our in vitro experiments were consistent with previous results in non-small-cell lung cancer [ 23 ]. Guan et al reported that HOXA10 mediated EMT in head and neck squamous cell carcinoma and was targeted by miR-195-5p [ 24 ]. However, their effects on radiosensitivity were to be investigated.…”

Emerging role of lncRNAs in drug resistance mechanisms in head and neck squamous cell carcinoma

“…Some studies have demonstrated the involvement of lncRNAs in the metabolism and disposition of anti-cancer drugs, influencing directly the development of DR ( 142 , 148 ). In HNSCC, DR has become an increasingly concerning challenge for the scientific community and clinicians ( 16 , 31 , 135 ). Along with many others, the long intergenic non-coding RNA 00958 (LINC00958) has been studied as apoptosis- and autophagy-related lncRNA in HNSCC as part of prognostic signature, establishing a worse overall survival rate of patients when the signature is present ( 140 , 150 ).…”

“…showed that the upregulation of LINC00461, LINC00402, and SFTA1P had suppressive effects on the homologous pleckstrin-homology (PH)-domain leucine-rich-repeat protein phosphatases (PHLPP2), reported previously as a tumor suppressor in colon cancer ( 210 ). In HNSCC, LINC00461 was highly expressed in 52 tissues analyzed, and it was found that LINC00461 downregulates the expression of miR-195 to subsequently upregulates the expression of HOXA10, promoting EMT and enhancing chemoresistance in HSNCC ( 16 ).…”

“…Nevertheless, drug resistance (DR) is still a key factor for HNSCC progression and poor prognosis ( 11 ). The detailed mechanisms of DR are not fully understood, but recent studies suggest that autophagy ( 12 – 14 ), epithelial–mesenchymal transition (EMT) ( 13 , 15 , 16 ), and cancer cell stemness ( 17 – 19 ) play a pivotal role in this major problem. Other mechanisms implied in DR are inactivation of the drug, multi-drug resistance, apoptosis suppression, alterations in the drug metabolism, epigenetic changes, changes in the drug targets, enhanced DNA-repair, and target gene amplification ( 20 ).…”

HSP90/c-Myc Axis regulated by lncRNA LINC00461 upregulation inhibited the ubiquitination of c-Myc and promotes glucose Metabolism and proliferation through LDHA in Triple-negative Breast Cancer

“…Although LINC00461 is related to several types of cancers, the role of LINC00461 in breast cancer is not fully understood [21][22][23] . Here, we demonstrated that LINC00461 was overexpressed in TNBC and was required for glucose metabolism and progression of proliferation in TNBC.…”