LncRNA ATP1A1-AS1 inhibits cell proliferation and promotes cell apoptosis in thyroid carcinoma by regulating the miR-620/IRF2BP2 axis

ntroduction

Thyroid carcinoma (THCA) is the most common malignancy of the endocrine system and is responsible for most mortality from endocrine cancer, even though it accounts for only 1% of human malignant neoplasms.

In the past several decades, its incidence is increasing worldwide partly because of overdiagnosis. Data at the Global Health Data Exchange website demonstrate an increase in incident cases (169%) and deaths (87%) of THCA from 1990 to 2017. So far, the etiology of THCA is not clear. In clinical practice, its pathogenesis may be associated with the following factors: iodine deficiency, radiation, thyrotropin chronic stimulation, sex hormones, goiter, and family factors. THCA is divided into three main subtypes: differentiated (follicular and papillary THCA), undifferentiated (anaplastic and poorly differentiated THCA), and medullary THCA. Management of THCA varies depending on specific tumor type. The differentiated THCA, as the most frequent subtype, has a significantly better outlook and is often curable with surgical resection and radioactive iodine . However, both rare subtype medullary and anaplastic THCAs show resistance to existing therapeutic modalities, the prognosis of which remains unfavorable. Molecular targeted therapy has been reported to help control tumor progression and prolong progression-free survival in advanced metastatic THCA.

Therefore, it is under urgent requirement to further understand and reveal the molecular mechanism underlying THCA.

MicroRNAs (miRNAs) are small non-coding single stranded RNAs of about 22 nucleotides that bind to the 3’ untranslated regions (UTRs) of downstream genes, resulting in their degradation or translational repression and ultimately downregulation of their expression.

Existing studies show that aberrantly expressed miRNAs are associated with tumor development, progression and response to therapy, implying their potential roles as diagnostic, prognostic and predictive biomarkers. Numerous miRNAs were reported to participate in THCA development. For instance, knockdown of miR-574-5p inhibits cell proliferation, migration, invasion and promotes cell apoptosis in THCA by upregulating FOXN3 expression. MiR-4319 impairs cell growth, motion, and EMT in THCA through targeting SMURF1. MiR-539 suppresses THCA cell invasion and migration through targeting CARMA1. The role of miR-620 as an oncogene was reported in multiple human cancers. MiR-620 can directly target and downregulate DCTD to inhibit cell apoptosis and promote cell growth, thereby leading to gemcitabine resistance in human breast cancer MDA-MB-231 cells. Blockage of miR‑620 suppresses the proliferation, migration and invasion of lung adenocarcinoma cells through directly modulating GPC5 expression. MiR-620 knockdown represses cell proliferative capability while it fosters cell apoptosis rate in vestibular schwannoma by upregulating ELK4.

However, the function of miR-620 in THCA is not clear.

Long non-coding RNAs (lncRNAs) comprise a cluster of RNAs over 200 nucleotides long, which lack protein-coding function.

LncRNAs are involved in various cellular processes, inactivation of chromosome X, genomic imprinting, and organ formation through changes in chromatin, transcription, and translation. Recent studies indicate that the aberrant expression of lncRNAs influences tumorigenesis and cancer progression. LncRNAs bind to chromatin, proteins, and RNAs to modulate cancer growth, motion, apoptosis, autophagy, and epithelial-mesenchymal transition (EMT). Increasing studies demonstrate that multiple lncRNAs participate in almost all processes of THCA development, including tumorigenesis, tumor proliferation and metastasis, and disease prognosis. LncRNA ATPase Na+/K+ transporting subunit alpha 1 antisense RNA 1 (ATP1A1-AS1) is a negative modulator of Na/K-ATPase α1, and inhibits human kidney cell proliferation and potentiates cell death. In the previous study, the ATP1A1-AS1 expression was significantly reduced along the more advanced T-stages in renal cell carcinoma. Moreover, ATP1A1-AS1 was identified by bioinformatic tools to be downregulated in THCA samples relative to normal tissues, suggesting that ATP1A1-AS1 might serve as a tumor suppressor in THCA.

Nevertheless, the potential molecular mechanism of how ATP1A1-AS1 regulates THCA development remains unclear.

Furthermore, lncRNAs are demonstrated to act as competing endogenous RNAs (ceRNAs) to modulate the tumorigenesis of multiple human cancers including THCA by sponging miRNAs. LncRNA LINC00460 induces THCA cell growth, migration and EMT through sponging miR-485-5p

LncRNA n384546 facilitates THCA progression and metastasis by sponging miR-145-5p. LncRNA ABHD11-AS1 enhances the abilities of cell growth and inhibits apoptosis in THCA via sponging miR-199a-5p.

Through bioinformatic analysis, ATP1A1-AS1 is predicted to have binding sites with miR-620. Therefore, this study is aimed to explore the mechanism of ATP1A1-AS1 as a ceRNA by sponging miR-620 in THCA development.

Herein, we intended to investigate the influence of ATP1A1-AS1 and the underlying molecular regulatory mechanism on THCA cell proliferation and apoptosis. We hypothesized that ATP1A1-AS1 inhibits cell proliferation and promotes cell apoptosis in THCA by binding with miR-620 and inhibiting the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2). Our findings might provide novel experimental basis for THCA targeted therapy.