A novel tumor suppressor ASMTL-AS1 regulates the miR-1228-3p/SOX17/β-catenin axis in triple‐negative breast cancer

Abstract

Background Triple-negative breast cancer (TNBC) is a special type of breast cancer that lacks effective therapeutic targets. There is a significant need to clarify its pathogenesis, so as to bring new targeted approaches for TNBC management. Here, we identified a long-non coding RNA (lncRNA) ASMTL-AS1 that linked to TNBC development and progression. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays were used to test gene and protein levels, respectively. The regulatory axis of miR-1228-3p/SOX17/β-catenin was determined by luciferase reporter and RNA pull-down assays. In vivo assay was conducted by using the nude mice model via subcutaneous transplantation of tumor cells. Results ASMTL-AS1 was significantly downregulated in TNBC tissues compared to normal tissues, which was closely associated with aggressive clinical features and unfavorable prognosis. Lentivirus-mediated ASMTL-AS1 overexpression evidently reduced the ability of TNBC cell colony formation, activity and invasion by more than 2.5 times. RNA pull-down and luciferase reporter assays revealed that miR-1228-3p directly bound to ASMTL-AS1, ASMTL-AS1 increased SOX17 expression via sponging and repressing miR-1228-3p. Subsequently, the upregulated SOX17 trans-suppressed β-catenin expression, resulting in the inactivation of carcinogenic Wnt/β-catenin signaling, thereby restraining TNBC cell growth and dissemination. Importantly, the xenograft tumor model showed that the ASMTL-AS1 overexpression significantly retarded tumor growth, and negatively regulated Wnt/β-catenin pathway. Conclusions Our data characterize a novel tumor suppressor in TNBC, restoration of ASMTL-AS1 may be a candidate therapeutic intervention for TNBC patients.

RETRACTED ARTICLE: The long non-coding RNA ASMTL-AS1 promotes hepatocellular carcinoma progression by sponging miR-1343-3p that suppresses LAMC1 (laminin subunit gamma 1)

“…However, its role in cancer may be context-dependent. For example, in breast cancer, the poor expression of ASMTL-AS1 was tightly linked with advanced stage and poor prognosis, and ASMTL-AS1 overexpression might inactivate the oncogenic Wnt/β-catenin pathway and subsequently retard breast cancer progression in vitro and in vivo [ 11 ]. In papillary thyroid carcinoma, ASMTL-AS1 exerts tumor-suppressive functions by suppressing the proliferative and metabolic phenotypes of tumor cells [ 10 ].…”

“…Among the multiple mechanisms by which lncRNAs interfere with gene expression, the competing endogenous RNA (ceRNA) mechanism has always been a research hotspot. ASMTL-AS1 has been reported to act as a tumor suppressor in thyroid carcinoma [ 10 ] and breast cancer [ 11 ] due to its ceRNA activity. However, a recent study showed that ASMTL-AS1 is highly expressed in HCC and favors malignant tumor phenotypes through miR-342-3p/YAP (Yes1-associated transcriptional regulator) signaling [ 12 ].…”

LncRNA ASMTL-AS1/microRNA-1270 differentiate prognostic groups in gastric cancer and influence cell proliferation, migration and invasion

“…Here, the level of ASMTL-AS1 in gastric cancer tissues and cells was quantitatively assessed by RT-qPCR. Previously, ASMTL-AS1 was reported to be significantly downregulated in triple-negative breast cancer and bladder cancer tissues [ 13 , 25 ]. Similarly, ASMTL-AS1 was significantly decreased in gastric tissues and cells when compared with the normal ones.…”

“…Because ASMTL-AS1 and miR-1270 were negatively correlated in expression level, miR-1270 mimic can reduce the fluorescence intensity of the wide-type ASMTL-AS1, and ASMTL-AS1 could pull down miR-1270. The ceRNA role of ASMTL-AS1 was also found in osteosarcoma with miR-342-3p, hepatocellular carcinoma with miR-1343-3p, and breast cancer by sponging miR-1228-3p [ 12 , 13 , 31 , 32 ]. Given the dysregulation of ASMTL-AS1 and miR-1270 in gastric cancer, whether ASMTL-AS1/miR-1270 regulatory loop affects the cell biological behaviors of gastric cells was further explored.…”

“…The assay to pull down miR-1270 by ASMTL-AS1 was carried out as previously mentioned [ 13 ]. In brief, HGC-27 and NCI-N87 cells were harvested, lysed, and sonicated.…”