Circ_0008039 supports breast cancer cell proliferation,migration, invasion,and glycolysis by regulating the miR‐140‐3p/SKA2 axis

Circular RNAs (circRNAs) have been shown to modulate gene expression and participate in the development of multiple malignancies. The purpose of this study was to investigate the role of circ_0008039 in breast cancer (BC). The expression of circ_0008039, miR‐140‐3p, and spindle and kinetochore‐associated protein 2 (SKA2) was detected by qRT‐PCR. Cell viability, colony formation, migration, and invasion were evaluated using methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, colony formation assay, and transwell assay, respectively. Glucose consumption and lactate production were measured using commercial kits. Protein levels of hexokinase II (HK2) and SKA2 were determined by western blot. The interaction between miR‐140‐3p and circ_0008039 or SKA2 was verified by dual‐luciferase reporter assay. Finally, a mouse xenograft model was established to investigate the roles of circ_0008039 in BC in vivo. We found that circ_0008039 and SKA2 were upregulated in BC tissues and cells, while miR‐140‐3p was downregulated. Knockdown of circ_0008039 suppressed BC cell proliferation, migration, invasion, and glycolysis. Moreover, miR‐140‐3p could bind to circ_0008039 and its inhibition reversed the inhibitory effect of circ_0008039 interference on proliferation, migration, invasion, and glycolysis in BC cells. SKA2 was verified as a direct target of miR‐140‐3p and its overexpression partially inhibited the suppressive effect of miR‐140‐3p restoration in BC cells. Additionally, circ_0008039 positively regulated SKA2 expression by sponging miR‐140‐3p. Consistently, silencing circ_0008039 restrained tumor growth via increasing miR‐140‐3p and decreasing SKA2. In conclusion, circ_0008039 downregulation suppressed BC cell proliferation, migration, invasion, and glycolysis partially through regulating the miR‐140‐3p/SKA2 axis, providing an important theoretical basis for treatment of BC.

Abbreviations

ANOVA

analysis of variance

BC

breast cancer

circRNAs

circular RNAs

DMSO

dimethyl sulfoxide

ECAR

extracellular acidification rate

ECL

enhanced chemiluminescence

FBS

fetal bovine serum

HK2

hexokinase II

MEGM

mammary epithelial growth medium

miR‐140‐3p

microRNA‐140‐3p

MTT

methylthiazolyldiphenyl‐tetrazolium bromide

PBS

phosphate‐buffered saline

PRKAR1B

protein kinase A regulatory subunit R1‐beta

SD

standard ± deviation

SKA2

spindle and kinetochore‐associated protein 2

     

Circ_0002623 promotes bladder cancer progression by regulating the miR‐1276/SMAD2 axis

Circular RNAs (circRNAs) are key regulatory factors in the development of multiple cancers. This study is targeted at exploring the effect of circ_0002623 on bladder cancer (BCa) progression and its mechanism. Circ_0002623 was screened out by analyzing the expression profile of circRNAs in BCa tissues. Circ_0002623, miR‐1276, and SMAD2 mRNA expression levels in clinical sample tissues and cell lines were detected through quantitative real‐time polymerase chain reaction (qRT‐PCR). After circ_0002623 had been overexpressed or silenced in BCa cells, the cell proliferation, migration, and cell cycle were evaluated by CCK‐8, BrdU, Transwell assay, and flow cytometry. Tumor xenograft model was used to validate the biological function of circ_0002623 in vivo. Bioinformatics analysis and dual‐luciferase reporter gene assay were conducted for analyzing and confirming, respectively, the targeted relationship between circ_0002623 and miR‐1276, as well as between miR‐1276 and SMAD2. The regulatory effects of circ_0002623 and miR‐1276 on the expression levels of TGF‐β, WNT1, and SMAD2 in BCa cells were detected by Western blot. We reported that, in BCa tissues and cell lines, circ_0002623 was upregulated, whereas miR‐1276 was downregulated. Circ_0002623 positively regulated BCa cell proliferation, migration, and cell cycle progression. Additionally, circ_0002623 could competitively bind with miR‐1276 to increase the expression of SMAD2, the target gene of miR‐1276. Furthermore, circ_0002623 could regulate the expression of TGF‐β and WNT1 via modulating miR‐1276 and SMAD2. This study helps to better understand the molecular mechanism underlying BCa progression.     

CircRNA EPHB4 modulates stem properties and proliferation of gliomas via sponging miR‐637 and up‐regulating SOX10

Gliomas are the most common type of primary brain tumors. CircRNA ephrin type‐B receptor 4 (circEPHB4) is a circular RNA derived from the receptor tyrosine kinase EPHB4. However, the clinical significance and the specific roles of circEPHB4 in gliomas and glioma cancer stem cells (CSC) have not been studied. Here, we found that circEPHB4 (hsa_circ_0081519) and SOX10 were up‐regulated and microRNA (miR)‐637 was down‐regulated in glioma tissues and cell lines. Consistently, circEPHB4 was positively correlated with SOX10 but negatively correlated with miR‐637. The altered expressions of these molecules were independently associated with overall survival of patients. CircEPHB4 up‐regulated SOX10 and Nestin by directly sponging miR‐637, thereby stimulating stemness, proliferation and glycolysis of glioma cells. Functionally, silencing circEPHB4 or increasing miR‐637 levels in glioma cells was sufficient to inhibit xenograft growth in vivo. In conclusion, the circEPHB4/miR‐637/SOX10/Nestin axis plays a central role in controlling stem properties, self‐renewal and glycolysis of glioma cells and predicts the overall survival of glioma patients. Targeting this axis might provide a therapeutic strategy for malignant gliomas.

Abbreviations

ANOVA

analysis of variance

circEPHB4

circRNA ephrin type‐B receptor 4

circRNA

circular RNA

HK2

hexokinase 2

mRNA

messenger RNA

miRNA

microRNA

PDK1

pyruvate dehydrogenase kinase 1

PI

propidium iodide

PKM2

pyruvate kinase M2

qRT‐PCR

quantitative real‐time polymerase chain reaction

RIP

RNA immunoprecipitation

SD

standard deviation

shcircEPHB4

short hairpin RNA specifically targeting circEPHB4

     

Downregulation of miR‐326 and its host gene β‐arrestin1 induces pro‐survival activity of E2F1 and promotes medulloblastoma growth

Persistent mortality rates of medulloblastoma (MB) and severe side effects of the current therapies require the definition of the molecular mechanisms that contribute to tumor progression. Using cultured MB cancer stem cells and xenograft tumors generated in mice, we show that low expression of miR‐326 and its host gene β‐arrestin1 (ARRB1) promotes tumor growth enhancing the E2F1 pro‐survival function. Our models revealed that miR‐326 and ARRB1 are controlled by a bivalent domain, since the H3K27me3 repressive mark is found at their regulatory region together with the activation‐associated H3K4me3 mark. High levels of EZH2, a feature of MB, are responsible for the presence of H3K27me3. Ectopic expression of miR‐326 and ARRB1 provides hints into how their low levels regulate E2F1 activity. MiR‐326 targets E2F1 mRNA, thereby reducing its protein levels; ARRB1, triggering E2F1 acetylation, reverses its function into pro‐apoptotic activity. Similar to miR‐326 and ARRB1 overexpression, we also show that EZH2 inhibition restores miR‐326/ARRB1 expression, limiting E2F1 pro‐proliferative activity. Our results reveal a new regulatory molecular axis critical for MB progression.

Abbreviations

ARRB1

β‐arrestin1

BTC

bulk tumor cell

CSCs

cancer stem cells

EZH2

enhancer of zeste homolog 2

GCP

granule cell progenitors

MB

medulloblastoma

OFC

oncosphere‐forming cell

     

Long non‐coding RNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1‐mediated mitochondrial fission

Long non‐coding RNAs (lncRNAs) are emerging as key molecules in various cancers, yet their potential roles in the pathogenesis of breast cancer are not fully understood. Herein, using microarray analysis, we revealed that the lncRNA RACGAP1P, the pseudogene of Rac GTPase activating protein 1 (RACGAP1), was up‐regulated in breast cancer tissues. Its high expression was confirmed in 25 pairs of breast cancer tissues and 8 breast cell lines by qRT‐PCR. Subsequently, we found that RACGAP1P expression was positively correlated with lymph node metastasis, distant metastasis, TNM stage, and shorter survival time in 102 breast cancer patients. Then, in vitro and in vivo experiments were designed to investigate the biological function and regulatory mechanism of RACGAP1P in breast cancer cell lines. Overexpression of RACGAP1P in MDA‐MB‐231 and MCF7 breast cell lines increased their invasive ability and enhanced their mitochondrial fission. Conversely, inhibition of mitochondrial fission by Mdivi‐1 could reduce the invasive ability of RACGAP1P‐overexpressing cell lines. Furthermore, the promotion of mitochondrial fission by RACGAP1P depended on its competitive binding with miR‐345‐5p against its parental gene RACGAP1, leading to the activation of dynamin‐related protein 1 (Drp1). In conclusion, lncRNA RACGAP1P promotes breast cancer invasion and metastasis via miR‐345‐5p/RACGAP1 pathway‐mediated mitochondrial fission.

Abbreviations

CDS

coding sequence

ceRNAs

competitive endogenous RNAs

Drp1

dynamin‐related protein 1

FFPE

formalin‐fixed paraffin‐embedded

lncRNAs

long non‐coding RNAs

miRNAs

microRNAs

RACGAP1

Rac GTPase activating protein 1

TCGA

The Cancer Genome Atlas

     

The KRAS/Lin28B axis maintains stemness of pancreatic cancer cells via the let‐7i/TET3 pathway

Increasing evidence demonstrates that Lin28B plays critical roles in numerous biological processes including cell proliferation and stemness maintenance. However, the molecular mechanisms underlying Lin28B nuclear translocation remain poorly understood. Here, we found for the first time that KRAS promoted Lin28B nuclear translocation through PKCβ, which directly bound to and phosphorylated Lin28B at S243. Firstly, we observed that Lin28B was upregulated in pancreatic cancer, contributing to cellular migration and proliferation. Furthermore, nuclear Lin28B upregulated TET3 messenger RNA and protein levels by blocking the production of mature let‐7i. Subsequently, increased TET3 expression could also promote the expression of Lin28B, thereby forming a Lin28B/let‐7i/TET3 feedback loop. Our results suggest that the KRAS/Lin28B axis drives the let‐7i/TET3 pathway to maintain the stemness of pancreatic cancer cells. These findings illuminate the distinct mechanism of Lin28B nuclear translocation and its important roles in KRAS‐driven pancreatic cancer, and have important implications for development of novel therapeutic strategies for this cancer.

Abbreviations

CCK‐8

cell counting kit‐8

CSC

cancer stem cells

IP

immunoprecipitation

MUT

mutant type

NLS

nuclear localization signal

PC

pancreatic cancer

PCSC

pancreatic cancer stem cells

PKC

protein kinase C

WT

wild‐type

     

TRIP13 promotes metastasis of colorectal cancer regardless of p53 and microsatellite instability status

Overexpression of TRIP13, a member of the AAA‐ATPase family, is linked with various cancers, but its role in metastasis is unknown in colorectal cancer (CRC). In the current study, we investigated the role TRIP13 in experimental metastasis and its involvement in regulation of WNT/β‐catenin and EGFR signaling pathways. Evaluation of formalin‐fixed paraffin‐embedded (FFPE) and frozen tissues of adenomas and CRCs, along with their corresponding normal samples, showed that TRIP13 was gradually increased in its phenotypic expression from adenoma to carcinoma and that its overexpression in CRCs was independent of patient''s gender, age, race/ethnicity, pathologic stage, and p53 and microsatellite instability (MSI) status. Moreover, liver metastases of CRCs showed TRIP13 overexpression as compared to matched adjacent liver tissues, indicating the biological relevance of TRIP13 in CRC progression and metastasis. TRIP13 knockdown impeded colony formation, invasion, motility, and spheroid‐forming capacity of CRC cells irrespective of their p53 and MSI status. Furthermore, xenograft studies demonstrated high expression of TRIP13 contributed to tumor growth and metastasis. Depletion of TRIP13 in CRC cells decreased metastasis and it was independent of the p53 and MSI status. Furthermore, TRIP13 interacted with a tyrosine kinase, FGFR4; this interaction could be essential for activation of the EGFR‐AKT pathway. In addition, we demonstrated the involvement of TRIP13 in the Wnt signaling pathway and in the epithelial–mesenchymal transition. Cell‐based assays revealed that miR‐192 and PNPT1 regulate TRIP13 expression in CRC. Additionally, RNA sequencing of CRC cells with TRIP13 knockdown identified COL6A3, TREM2, SHC3, and KLK7 as downstream targets that may have functional relevance in TRIP13‐mediated tumor growth and metastasis. In summary, our results demonstrated that TRIP13 promotes tumor growth and metastasis regardless of p53 and MSI status, and indicated that it is a target for therapy of CRC.

Abbreviations

CIN

chromosomal instability

CRC

colorectal cancer

EMT

epithelial–mesenchymal transition

FFPE

formalin‐fixed, paraffin‐embedded

LEF

lymphoid enhancer factor

MS

microsatellite

MSI

microsatellite instable

MSS

microsatellite stable

NSG

NOD/SCID/IL2γ receptor‐null

NT

nontargeting

SAC

spindle assembly checkpoint

TCF

T‐cell factor

TRIP13

thyroid hormone receptor interactor 13

UAB

University of Alabama at Birmingham

     

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR

androgen receptor

ATP

adenosine triphosphate

CN

copy number

CPT1

carnitine palmitoyltransferase I

CS

citrate synthase

EMT

epithelial–mesenchymal transition

ET

electron transfer‐state

FABP

fatty acid‐binding protein

LD

lipid droplet

OA

oleic acid

PCa

prostate cancer

PPAR

peroxisome proliferator‐activated receptor

PPRE

peroxisome proliferator‐activated receptor response element

TZD

thiazolidinediones

     

TGFβ promotes YAP‐dependent AXL induction in mesenchymal‐type lung cancer cells

The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.

Abbreviations

AUC

area under the curve

AXL

AXL receptor tyrosine kinase

BCL2

B‐cell lymphoma 2

CTD2

cancer target discovery and development

CTGF

connective tissue growth factor

DEG

differentially expressed genes

DOXO

doxorubicin

EMT

epithelial–mesenchymal transition

Eto

etoposide

FDA

Food and Drug Administration

ITGB3

integrin beta‐3

MAPK

mitogen‐activated protein kinase

MMP2

matrix metalloproteinase‐2

MMP9

matrix metalloproteinase‐9

mRNA

messenger RNA

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

SBE

SMAD binding element

SERPINE1

serpin family E member 1

siRNA

small interfering RNA

ssGSEA

single‐sample gene set enrichment analysis

TCGA

The Cancer Genome Atlas

TGFβ

transforming growth factor beta

YAP

Yes‐associated protein

YAP8SA

mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP

ZEB1

zinc finger E‐box binding homeobox 1

ZEB2

zinc finger E‐box‐binding homeobox 2

     

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non‐small cell lung cancer

Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid‐lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remains unclear. Here, we found that simvastatin treatment effectively promoted antiproliferative effects and modulated lipid metabolism‐related pathways in non‐small cell lung cancer (NSCLC) cells and that the antiproliferative effects of statins were potentiated by overexpression of acyl‐CoA synthetase long‐chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high‐grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.

Abbreviations

3‐HMGCR

3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase

95% CI

95% confidence intervals

ACSL3

acyl‐CoA synthetase long‐chain family member 3

ACSLs

long‐chain acyl‐CoA synthetases

ALP

alkaline phosphatase

APOA1

apolipoprotein A1

ATCC

American Type Culture Collection

CASP9

caspase 9

ECAR

extracellular acidification rate

ECOG

Eastern Cooperative Oncology Group

EMT

epithelial‐to‐mesenchymal transition

ER

endoplasmic reticulum

FAs

fatty acids

FFPE

formalin‐fixed, paraffin‐embedded

GTEx

genotype‐tissue expression

HR

Hazard ratio

IC50

half‐maximal inhibitory concentration

LDH

lactate dehydrogenase

MTT

3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium

NID1

nidogen 1

No ORF

no open reading frame

NSCLC

non‐small cell lung cancer

OCR

oxygen consumption rate

OS

overall survival

PGE2

prostaglandins E2

RETN

resistin

TCGA

The Cancer Genome Atlas

TMA

tumor tissue microarray

     

circUSP34 accelerates osteosarcoma malignant progression by sponging miR‐16‐5p

Osteosarcoma (OS) is a primary and highly malignant mesenchymal tissue tumor. The specific pathological mechanism underlying disease initiation or progression remains unclear. Circular RNAs (circRNAs) are a type of covalently circular RNA with a head‐to‐tail junction site. In this study, we aimed to investigate the sponging mechanism between circRNAs and microRNAs (miRNAs) in OS. Based on the inhibited effect of miR‐16‐5p reported on OS, circUSP34 was analyzed as a sponge of miR‐16‐5p via Starbase. We found that circUSP34 promoted the proliferation, migration, and invasion of OS in vitro and in vivo. circUSP34 increased but miR‐16‐5p decreased in OS by qRT‐PCR. Function assays showed that the malignancy of OS cells, including proliferation, migration, and invasion, was inhibited after knocking out circUSP34. Western blotting results showed that the expression level of vimentin and Ki‐67 decreased. Similarly, miR‐16‐5p mimic compromised the proliferation, migration, and invasion of OS cells. FISH assay results indicated that circUSP34 and miR‐16‐5p were colocalized in the cytoplasm. The sponging mechanism of circUSP34 and miR‐16‐5p was verified by dual‐luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down assays. Interestingly, the miR‐16‐5p inhibitor partly reversed the inhibitory effect of sh‐circUSP34 on the malignancy of OS cells. Further, mice tumors for IHC indicated that vimentin, N‐cadherin, and Ki‐67 protein expression decreased, but E‐cadherin protein expression increased. Collectively, circUSP34 promoted OS malignancy, including proliferation, migration, and invasion, by sponging miR‐16‐5p. It can serve as a potential therapeutic target and biomarker.     

SIK2 represses AKT/GSK3β/β‐catenin signaling and suppresses gastric cancer by inhibiting autophagic degradation of protein phosphatases

Salt‐inducible kinase 2 (SIK2) is an important regulator in various intracellular signaling pathways related to apoptosis, tumorigenesis and metastasis. However, the involvement of SIK2 in gastric tumorigenesis and the functional linkage with gastric cancer (GC) progression remain to be defined. Here, we report that SIK2 was significantly downregulated in human GC tissues, and reduced SIK2 expression was associated with poor prognosis of patients. Overexpression of SIK2 suppressed the migration and invasion of GC cells, whereas knockdown of SIK2 enhanced cell migratory and invasive capability as well as metastatic potential. These changes in the malignant phenotype resulted from the ability of SIK2 to suppress epithelial–mesenchymal transition via inhibition of AKT/GSK3β/β‐catenin signaling. The inhibitory effect of SIK2 on AKT/GSK3β/β‐catenin signaling was mediated primarily through inactivation of AKT, due to its enhanced dephosphorylation by the upregulated protein phosphatases PHLPP2 and PP2A. The upregulation of PHLPP2 and PP2A was attributable to SIK2 phosphorylation and activation of mTORC1, which inhibited autophagic degradation of these two phosphatases. These results suggest that SIK2 acts as a tumor suppressor in GC and may serve as a novel prognostic biomarker and therapeutic target for this tumor.

Abbreviations

AMPK

AMP‐activated protein kinase

Co‐IP

co‐immunoprecipitation

EMT

epithelial–mesenchymal transition

GAPDH

glyceraldehyde‐3‐phosphate dehydrogenase

GC

gastric cancer

GEO

Gene Expression Omnibus

H&E

hematoxylin and eosin

IHC

immunohistochemistry

mTOR

mechanistic target of rapamycin

NC

negative control

PHLPP

PH domain leucine‐rich repeat protein phosphatase

PP2A

protein phosphatase 2A

qRT‐PCR

quantitative real‐time polymerase chain reaction

SIK2

salt‐inducible kinase 2

TCF/LEF

T cell factor/lymphoid enhancer‐binding factor

TCGA

The Cancer Genome Atlas

     

Hsa_circ_0005576 promotes osimertinib resistance through the miR‐512‐5p/IGF1R axis in lung adenocarcinoma cells

Osimertinib is a third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR‐TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib‐resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR‐512‐5p and subsequently upregulate the miR‐512‐5p‐targeted insulin‐like growth factor 1 receptor. Rescue assays indicated that miR‐512‐5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR‐512‐5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.