The lncRNA ADAMTS9-AS2 Regulates RPL22 to Modulate TNBC Progression via Controlling the TGF-β Signaling Pathway

Abstract

BackgroundLong non-coding RNAs (lncRNAs) are key regulators of triple-negative breast cancer (TNBC) progression, but further work is needed to fully understand the functional relevance of these non-coding RNAs in this cancer type. Herein, we explored the functional role of the lncRNA ADAMTS9-AS2 in TNBC.MethodsNext-generation sequencing was conducted to compare the expression of different lncRNAs in TNBC tumor and paracancerous tissues, after which ADAMTS9-AS2differential expression in these tumor tissues was evaluated via qPCR. The functional role of this lncRNA was assessed by overexpressing it in vitro and in vivo. FISH and PCR were used to assess the localization of ADAMTS9-AS2within cells. Downstream targets of ADAMTS9-AS2 signaling were identified via RNA pulldown assays and transcriptomic sequencing.ResultsThe expression ofADAMTS9-AS2 was decreased in TNBC tumor samples (P < 0.05), with such downregulation being correlated with TNM stage, age, and tumor size. Overexpressing ADAMTS9-AS2 promoted the apoptotic death and cell cycle arrest of tumor cells in vitro and inhibited tumor growth in vivo. From a mechanistic perspective, ADAMTS9-AS2 was found to control the expression of RPL22 and to thereby modulate TGF-β signaling to control TNBC progression.ConclusionADAMTS9-AS2 controls the expression of RPL22 and thereby regulates TNBC malignancy via the TGF-β signaling pathway.

Differential Expression of Necroptosis-Related Genes with regulating lncRNA in Triple Negative Breast Cancer to Predict Prognosis and Immunotherapy Response

“…Several bioinformatic studies found that high expression of Z68871.1 and SPRY4-AS1 were correlated with worse OS in solid tumors including BC, HCC, and squamous cell carcinoma [69][70][71][72][73]. High expression of ADAMTS9-AS2 was related to a better treatment response and prognosis in BC [74,75], which was coherent with our results. However, high expression of COL4A2-AS1, CCDC144NL-AS1, and ADAMTS9-AS2 were related to proliferation and worse prognosis of breast, gastric, colorectal cancer, HCC, and lung cancer [76][77][78][79][80][81].…”

Identification of long noncoding RNAs downregulated specifically in ovarian high‐grade serous carcinoma

“…ADAMTS9‐AS2 controls cancer cell behavior by modulating TGF‐β signaling in breast cancer and tongue squamous cell carcinoma. 41 , 42 Interestingly, TGFβ is reported to promote cell migration and metastasis by inducing epithelial‐mesenchymal transition (EMT), while inhibiting cell proliferation by inducing G1 phase cell cycle arrest in human oral cancer cells. 43 In addition, ADAMTS9‐AS2 regulates FOXO1 in clear cell RCC.…”

Unboxing the network among long non-coding RNAs and TGF-β signaling in cancer

“…Additional lncRNAs reported as potentially poor prognostic markers for TNBC patients were the tumor suppressor candidate 7 ( TUSC7 ) and ADAMTS9 antisense RNA 2 ( ADAMTS9-AS2 ) ( 17 , 18 ). TUSC7 can bind to miR-1224-3p , and its overexpression decreased cell motility and promoted the sensitivity of MDA-MB-468 cells to cytotoxic drugs, while TUSC7 knockdown in MDA-MB-231 cells enhanced TGFBR2 levels, suggesting a negative role of TUSC7 on TGF-β signaling ( 18 ).…”

“…TUSC7 can bind to miR-1224-3p , and its overexpression decreased cell motility and promoted the sensitivity of MDA-MB-468 cells to cytotoxic drugs, while TUSC7 knockdown in MDA-MB-231 cells enhanced TGFBR2 levels, suggesting a negative role of TUSC7 on TGF-β signaling ( 18 ). Furthermore, ADAMTS9-AS2 can interact with and modulate the expression of the ribosomal protein L22 (RPL22) ( 17 ). These data were further correlated with the translational downregulation of TGFBRI and SMAD2 , thereby modulating TGF-β signaling negatively.…”