SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis

Du, Feng; Chen, Jie; Líu, Hao; Cai, Yanhui; Cao, Tianyu; Han, Wei; Yi, Xiaofang; Qian, Meirui; Tian, Dean; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Xia, Limin

doi:10.1038/s41419-019-1481-9

Cited by 64 publications

(55 citation statements)

References 45 publications

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“…Sex determining region Y-box protein (SOX) 12 (SOX12), an important member of the SOX family, was reported to play crucial roles in cardiac, neuronal and mesenchymal development processes [18]. Several studies reported that SOX12 is up-regulated and contribute to initiation and progression of several cancers, including gastric cancer [19], colorectal cancer [20], hepatocellular carcinoma [21] and lung cancer [22]. Recently a study showed that SOX12 expression was up-regulated in breast cancer tissues, and knockdown of SOX12 inhibited breast cancer proliferation, migration and invasion in vitro, and suppressed tumor growth in vivo [23], suggesting that SOX12 play an oncogenic role in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Functional analyses of microRNA-326 in breast cancer development

Shen

Zhang

et al. 2019

Bioscience Reports

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MicroRNA-326 (miR-326) was reported to be dysregulated and involved in the progression of multiple cancers. However, the clinical significance, biological role and underlying mechanism of miR-326 in the carcinogenesis of breast cancer are still unclear. In the present study, we showed that miR-326 was down-regulated in human breast cancer tissues and cell lines. Our results also revealed that miR-326 overexpression significantly suppressed breast cancer cell proliferation, migration and invasion, and induced cell cycle arrest at G1/G0 phase. Furthermore, Sex determining region Y-box (SOX) protein 12 (SOX12), a known oncogene, was identified as a direct target of miR-326 by luciferase reporter assay. Moreover, miR-326 expression was inversely correlated with SOX12 mRNA expression levels in human breast cancer specimens. Overexpression of SOX12 partially rescued the inhibitory effect on cell proliferation, migration and invasion in breast cancer cells caused by miR-326 overexpression. These findings suggested that miR-326 might play a suppressive role in breast cancer, at least in part, by targeting SOX12, rendering miR-326 a promising therapeutic target for breast cancer.

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Section: Introductionmentioning

confidence: 99%

Functional analyses of microRNA-326 in breast cancer development

Shen

Zhang

et al. 2019

Bioscience Reports

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“…In addition, Du et al (29) demonstrated that SOX12 may represent a novel prognostic biomarker and regulator of gastric cancer metastasis via upregulating MMP7 and insulin-like growth factor 1. According to a previous study, SOX12 may serve as a prognostic biomarker of CRC, and promotes CRC cell proliferation and metastasis via regulating asparagine synthesis (30). In the present study, western blot analysis demonstrated that NRSN2-knockdown decreased SOX12 expression, while NRSN2 overexpression upregulated SOX12 expression, indicating that NRSN2 may exert accelerative effects on CRC progression by recruiting SOX12.…”

Section: Discussionsupporting

confidence: 67%

Neurensin‑2 promotes proliferation, invasion and migration of colorectal cancer cells via interaction with SOX12

Wang

Yang

2020

Oncol Lett

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Colorectal cancer (CRC) is the third most common malignant type of tumor worldwide. Neurensin-2 (NRSN2) is a small neuronal membrane protein associated with tumorigenesis. Therefore, the present study aimed to investigate the association between NRSN2 and CRC, and further examined the underlying mechanism of its effect on CRC metastasis. Human CRC SW620 cells were used to determine the biological functions of NRSN2 in CRC. Cell counting Kit-8 (CCK8), colony formation, wound-healing and transwell assays were performed to evaluate the role of NRSN2 on survival and metastasis of SW620 cells. The interaction between NRSN2 and SOX12 was determined via bioinformatics analysis and confirmed using immunoprecipitation. It was identified that NRSN2 was highly expressed in CRC cells and served a critical role in CRC cell survival compared with in healthy colon epithelial cells. Furthermore, NRSN2-knockdown inhibited the proliferation, invasion and migration of SW620 cells, while NRSN2 overexpression promoted these cellular processes. Additionally, it was demonstrated that NRSN2 could recruit SOX12 in SW620 cells. NRSN2-knockdown decreased SOX12 expression, while NRSN2 overexpression upregulated SOX12 expression. Overall, the present results suggested NRSN2 as a novel biomarker for CRC diagnosis and identified NRSN2 as a potential therapeutic target for CRC treatment.

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“…Consistent with the observations in the patients, downregulation or overexpression of the three enzymes had opposite effects on cell proliferation and metastasis development. The role of Asn in these effects was confirmed by the inhibition of tumor growth and metastasis by ASNase (71).…”

Section: Asns In Cancer: Beyond Asn Synthesis?mentioning

confidence: 84%

“…Looking for regulators of the metastatic behavior in human colon cancer, Duquet et al (70) identified the sex-determining region Y (SRY)-box, member 12 (SOX12), as a suppressor of metastatic behavior of HT29 xenografts. However, in a more recent paper, Du et al (71) demonstrate that in two independent, large colorectal cancer cohorts HIF-1α-mediated SOX12 overexpression is not only associated with a metastatic behavior, but also with a poor prognosis. Moreover, it also enhanced cell proliferation in vitro.…”

Section: Asns In Cancer: Beyond Asn Synthesis?mentioning

confidence: 98%

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

et al. 2020

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Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-essential amino acid asparagine (Asn) from aspartate (Asp) and glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS protein expression is a hallmark of Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-Asparaginase (ASNase) for ALL therapy, the first example of anti-cancer treatment targeting a tumor-specific metabolic feature. Other hematological and solid cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected cancer models, suggesting a variable and tumor-specific role of the enzyme in cancer. Recent evidence indicates that, beyond its canonical role in protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and cancer tissues, with particular attention to the fueling of Asn exchange between cancer cells and the tumor microenvironment.

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SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis

Cited by 64 publications

References 45 publications

Functional analyses of microRNA-326 in breast cancer development

Functional analyses of microRNA-326 in breast cancer development

Neurensin‑2 promotes proliferation, invasion and migration of colorectal cancer cells via interaction with SOX12

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

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