Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells

Miyamoto, Tsutomu; Kashima, Hiroyasu; Yumura, Yasushi; Kobara, Hisanori; Asaka, Ryoichi; Ando, Hirofumi; Higuchi, Satoshi; Ito, Koichi; Mvunta, David Hamisi; Shiozawa, Tanri

doi:10.1371/journal.pone.0155220

Cited by 35 publications

(38 citation statements)

References 41 publications

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“…Moreover, as mentioned earlier, p53 was found to be downregulated in NGAL knockdown cells. Our results were similar to previous studies where NGAL was shown to regulate the expression of p53 [45,46]. and decreases autophagy.…”

Section: Discussionsupporting

confidence: 93%

NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration, and Chemoresistance

Monisha

Roy

Banik

et al. 2018

Preprint

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Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer. Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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Section: Discussionsupporting

confidence: 93%

NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration, and Chemoresistance

Monisha

Roy

Banik

et al. 2018

Preprint

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“…LCN2, also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), belongs to the lipocalin family. Recently, LCN2 was reported to potentially play important roles in tumour progression and chemoresistance in many kinds of cancer 17 . Hence, we selected LCN2 for further analysis.…”

Section: Lcn2 Was Up-regulated After Cisplatin Treatment and Down-regmentioning

confidence: 99%

“…Chemotherapy sensitivity may be due to changes in gene expression caused by epigenetic changes such as DNA methylation at the promoter after treatment 18 . Methylation at promoters has been reported to play an important role in regulating LCN2 expression 17 . So we evaluated methylation status after vitamin D and cisplatin treatment.…”

Section: Lcn2 Was Up-regulated After Cisplatin Treatment and Down-regmentioning

confidence: 99%

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Huang

Zhang

et al. 2019

Cell Death Dis

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Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.

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“…Although it is now well-established that LCN2 has fundamental modulator activities during hepatic insult, there is still some work that remains to be done prior announcing LCN2 as a therapeutic target. Currently, initial studies that use anti-LCN2 antibodies (Tarín et al, 2016 ), siRNAs or shRNAs targeting LCN2 (Volpe et al, 2013 ; Miyamoto et al, 2016 ), specialized nanoparticle-based theranostic agents (Guo et al, 2016 ), or modulators that impacts LCN2 receptor expression (Cui et al, 2008 ) in different settings are initiated. In addition, the design of therapeutic small-molecule inhibitors for LCN2 was recently proposed (Suk, 2016 ).…”

Section: Lcn2 In Therapymentioning

confidence: 99%

Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy

2016

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Lipocalin 2 (LCN2) is a secreted protein that belongs to the Lipocalins, a group of transporters of small lipophilic molecules such as steroids, lipopolysaccharides, iron, and fatty acids in circulation. Two decades after its discovery and after a high variety of published findings, LCN2's altered expression has been assigned to critical roles in several pathological organ conditions, including liver injury and steatosis, renal damage, brain injury, cardiomyopathies, muscle-skeletal disorders, lung infection, and cancer in several organs. The significance of this 25-kDa lipocalin molecule has been impressively increased during the last years. Data from several studies indicate the role of LCN2 in physiological conditions as well as in response to cellular stress and injury. LCN2 in the liver shows a protective role in acute and chronic injury models where its expression is highly elevated. Moreover, LCN2 expression is being considered as a potential strong biomarker for pathological conditions, including rheumatic diseases, cancer in human organs, hepatic steatosis, hepatic damage, and inflammation. In this review, we summarize experimental and clinical findings linking LCN2 to the pathogenesis of liver disease.

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Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells

Cited by 35 publications

References 41 publications

NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration, and Chemoresistance

NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration, and Chemoresistance

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy

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