Targeting cancer stem cell signature gene SMOC-2 Overcomes chemoresistance and inhibits cell proliferation of endometrial carcinoma

Lu, Huan; Ju, Dan-dan; Yang, Guangdong; Zhu, Linyan; Yang, Xiaomei; Li, Jun; Song, Weiwei; Wang, Jin-hao; Zhang, Can-can; Zhang, Zhigang; Zhang, Rong

doi:10.1016/j.ebiom.2018.12.044

Cited by 79 publications

(74 citation statements)

References 45 publications

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“…Its gene product is a matricellular protein that stimulates endothelial cell migration and proliferation, and angiogenic activity [27,28]. This study also found that targeting the cancer stem cell signature gene, SMOC-2, inhibited endometrial carcinoma cell proliferation and overcame the chemoresistance [29]. Smoc2 potentiates carcinoma cell proliferation through cell cycle progression promotion [15,30].…”

Section: Discussionmentioning

confidence: 68%

Knockdown of hsa_circ_0074298 suppressed the progression of pancreatic cancer by targeting the miR-519/SMOC2 axis

Chen

Wang

et al. 2020

Preprint

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BACKGROUND: Pancreatic cancer (PC) is among the most malignant tumors in the digestive system because of its fast progression, metastasis, as well as its resistance to chemotherapy. Former studies found that circRNAs that were differentially expressed were correlated with progression and gemcitabine (GEM)-resistance in PC, and hsa_circ_0074298 aberrant expression played a role in PC progression, but the regulatory mechanism was unclear. METHODS: RT-qPCR was used to detect hsa_circ_0074298 expression in PC cell lines. CCK8, colony formation, and Transwell assays were used to evaluate the effect of hsa_circ_0074298 on PC cell migration and proliferation. Bioinformatics and luciferase reporter experiments were used to characterize the regulatory mechanism. Nude mouse xenografts were generated to examine the effect of hsa_circ_0074298 on tumor growth. RESULTS: The present study showed that hsa_circ_0074298 expression increased significantly in both PC cell lines and PC tissues. Downregulation of hsa_circ_0074298 caused a significant decrease in PC cell proliferation and in nude mouse xenograft growth. Hsa_circ_0074298 silencing also increased chemotherapy sensitivity to GEM. Bioinformatics analysis indicated that hsa_circ_0074298 was a miR-519 sponge and that the SMOC2 gene was a miR-519 target. MiR-519 downregulation or SMOC2 overexpression restored cell proliferation, migration, and chemoresistance after hsa_circ_0074298 silencing. The dual luciferase reporter assay showed that hsa_circ_0074298 interacted with miR-519, and miR-519 binding to the SMOC2 3′-UTR then suppressed posttranscriptional SMOC2 expression. CONCLUSIONS: Taken together, hsa_circ_0074298 functioned as a tumor promoter through a novel miR-519/SMOC2 axis, highlighting its possibility as a potential therapy for PC.

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Section: Discussionmentioning

confidence: 68%

Knockdown of hsa_circ_0074298 suppressed the progression of pancreatic cancer by targeting the miR-519/SMOC2 axis

Chen

Wang

et al. 2020

Preprint

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“…SMOC2 is an important structural anchor in the ECM networks of cartilage, like other members of the BM40/SPARC family, but SMOC2 can also interact with receptors on the cell surface, acting as a regulator of cell–matrix interaction to activate or inactivate some signaling pathways. Previous evidence demonstrated that SMOC2 is involved in the pathways fibroblast growth factor or vascular endothelial growth factor signaling [ 28 ] , TGF-β1-SMAD2/3 [ 29, 30 ] , WNT/β-catenin [ 31 ] , and BMP-SMAD1/5/9 [ 14, 23, 32 ] , which play an important role in chondrogenesis. Considering the importance of the BMP-SMAD1/5/9 pathway in endochondral bone formation [ 33–36 ] , we assessed whether the mutant Smoc2 affected the BMP-SMAD1/5/9 pathway.…”

Section: Discussionmentioning

confidence: 99%

A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

Long

Lin

Shi

et al. 2020

Preprint

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Abstract： Previously study showed that SMOC, a matricellular protein, inhibits BMP 20 signaling downstream of its receptor via activation of mitogen-activated protein kinase 21 (MAPK) signaling. In our study, exome sequencing revealed a missense mutation 22 (c.1076T>G, p.Leu359Arg) in EC domain of SMOC2 in a Chinese family with 23 multiple epiphyseal disease (MED). The pathogenicity of this SMOC2 variant was 24 verified by Smoc2 L359R/L359R knock-in mice. Of note, decreasing phosphorylation of 25 SMAD1/5/9 was detected in growth plates and primary chondrocytes from 26Smoc2 L359R/L359R mice. Furthermore, binding affinity of mutant SMOC2 with collagen 27 IX and HSPG in the extracellular matrix of cartilage were reduced while binding 28 affinity with BMPRIB was intact. In addition, in contrast to previously results, that 29 SMOC2 cannot antagonize BMP activity in the presence of a constitutively activated 30 BMP receptor. These results support that SMOC2 with p.Leu359Arg variant act as an 31 antagonist of canonical BMP pathway by competitively binding with BMP receptors. 32 33 Introduction 34Multiple epiphyseal dysplasia (MED, MIM 132400) is a genotypically and 35 phenotypically heterogeneous skeletal dysplasia and chondrodysplasia that affects 36 epiphysis of long bones [1, 2] . MED is characterized by early-onset arthritis, especially in 37 hip and knee joints, which results in joint pain and stiffness, waddling gait in early 38 childhood, and mild to moderate shortness of stature. Eight disease genes, which may 39 be inherited in an autosomal dominant or recessive pattern, have been identified. 40Autosomal dominant variants include collagen oligomeric matrix protein (COMP) [3, 4] , 41 collagen type IX α-1 (COL9A1) [5] , collagen type IX α-2 (COL9A2) [6] , collagen type IX 42 α-3 (COL9A3) [7] , matrilin-3 (MATN3) [8] , and collagen type II α-1 (COL2A1) [9] . 43Autosomal recessive variants are the sulfate transporter gene (SLC26A2) and 44 calcium-activated nucleotidase-1 (CANT1) [10, 11] . All proteins encoded by the known 45 MED-associated genes are involved in maintaining the structural integrity of the 46 cartilage extracellular matrix (ECM). All variants in these genes account for the 47 molecular basis of about 70% of MED cases [11] . However, a number of MED cases 48 have no identifiable genetic mutation, and additional genetic etiologies of MED remain 49 to be identified. 50 SPARC-related modular calcium binding 2 (SMOC2) and SMOC1, its closest 51 homolog, are members of the protein family BM-40 (also known as secreted protein 52 acidic and rich in cysteines [SPARC] or osteonectin) [12, 13] . BM-40 is a prototypic 53 collagen-binding matricellular protein that participates in regulating cell-matrix 54 4 interactions, in particular influencing bone mineralization, wound repair and other 55 biological functions. The BM-40 family of modular extracellular proteins is 56 characterized by a follistatin-like (FS) domain as well as an extracellular 57 calcium-binding (EC) domain with two EF-hand calcium-b...

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“…In previous study, it has been demonstrated that chemoresistance is associated with the crosstalk between leptin-induced Notch and IL-1 signaling in endometrial cancer. At the most recent, a study pointed that cancer stem cells are responsible for cancer proliferation and chemoresistance [20], it was found that SPARC-related modular calcium binding 2 (SMOC-2) drive the endometrial cancer chemoresistance functional as a endometrial cancer stem cell molecule. Similarly, Caner Saygin et.al reported that CD55, as unique signaling node, drives self-renewal and chemoresistance in endometrioid cancers [29].…”

Section: Discussionmentioning

confidence: 99%

“…It has been found that many compounds are able to inhibit the expression of Nrf2 protein and its downstream target genes containing an enhancer sequence known as the antioxidant response element (ARE) [14][15][16][17]. Some of the target genes have the function to detoxi cation and removal of pharmacologic agents, which may contribute to chemoresistance [18][19][20]. Therefore, targeting Nrf2 and Nrf2-regulated downstream gene is a good strategy for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Stigmasterol Sensitizes Endometrial Cancer Cells to Chemotherapy By repressing Nrf2 Signal Pathway

Liao

Zhu

Bai

et al. 2020

Preprint

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Background: Chemoresistance reduces the 5-year survival rate of endometrial cancer patient, which is the current major obstacle for cancer therapy. Increasing evidence state that Nrf2 contributes to chemoresistance in several kinds of cancer. However, its role in endometrial cancer cells remains unclarified. Methods: Immunohistochemistry staining was used to detect the expression of Nrf2 in normal patient and endometrial cancer patient. Stable transfection Ishikawa cell line with high level of Nrf2 was established to evaluate its role in chemoresistance. Dot blot assays were used to assess global hydroxymethylation level after stigmasterol treatment. Cellular growth profile was detected by CCK8 assay. Western blot was used to evaluate the changes of the target molecules after various treatments. Results: Nrf2 is overexpressed in endometrial cancer tissues compared with the normal endometrium. Overexpression of Nrf2 resulted in decrease sensitivity to cisplatin. In addition, stigmasterol has been identified as a novel Nrf2 inhibitor. It enhanced the sensitivity of endometrial cancer cells to cisplatin, and the underlying mechanism is that stigmasterol declines the Nrf2 protein level. Conclusions: Our findings identified stigmasterol as a new potential inhibitor of Nrf2 and highlight a critical role of stigmasterol in overcoming chemoresistance in endometrial cancer therapy.

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Targeting cancer stem cell signature gene SMOC-2 Overcomes chemoresistance and inhibits cell proliferation of endometrial carcinoma

Cited by 79 publications

References 45 publications

Knockdown of hsa_circ_0074298 suppressed the progression of pancreatic cancer by targeting the miR-519/SMOC2 axis

Knockdown of hsa_circ_0074298 suppressed the progression of pancreatic cancer by targeting the miR-519/SMOC2 axis

A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

Stigmasterol Sensitizes Endometrial Cancer Cells to Chemotherapy By repressing Nrf2 Signal Pathway

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