High expression of AKR1C1 is associated with proliferation and migration of small-cell lung cancer cells

Tian, He; Li, Xingxing; Jiang, Wenli; Lv, Cuicui; Sun, Wenjuan; Huang, Chun; Chen, Ruohua

doi:10.2147/lctt.s90694

Cited by 31 publications

(36 citation statements)

References 34 publications

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“…Results of RT-qPCR and western blot confirmed AKR1C1 mRNA and protein levels were lower following WA treatment. Tian et al ( 24 ) demonstrated that high expression of AKR1C1 gene was associated with progression and poor prognosis of lung cancer. AKR1C1 is associated with numerous important biological processes, including the oxidation reduction and carcinogenesis of a number of vertebrate species ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF‑1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase‑3 signaling pathway in small cell lung cancer

Jiang

Meng

et al. 2018

Oncol Lett

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Wentilactone A (WA), a marine-derived compound, inhibits proliferation of NCI-H446, as demonstrated by previous research; however, the anti-SCLC mechanism underlying WA was not fully investigated. The present study aimed to investigate the anti-SCLC mechanism underlying WA in vitro and in vivo. Cell Counting Kit-8 was used to assay cell growth, flow cytometry was conducted to analyze cell apoptosis and nude mice xenografts were used to examine SCLC growth following WA treatment. Bioinformatics was used for verification of the target gene of WA. Reverse transcription-quantitative polymerase chain reaction and western blot were used to examine aldo-keto reductase family 1 member C1 (AKR1C1) mRNA and protein levels, and AKR1C1-associated proteins prior to and following WA treatment. Cell growth, apoptosis and growth of nude mice xenografts were assayed prior to and following transfection with AKR1C1 knockdown or overexpression carriers, respectively. It was determined that AKR1C1 was a target gene of WA. Decreased AKR1C1 expression and WA treatment promoted apoptosis in SCLC via the insulin like growth factor-1 receptor/insulin receptor substrate 1/phosphoinositide 3-kinase/AKT/nuclear factor-erythroid 2-associated factor 2/Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein/Caspase-3 pathway. WA attenuated the proliferation and induced the apoptosis of SCLC cells in vitro and in vivo by targeting the AKR1C1 gene. WA may be a novel AKR1C1-targeted drug candidate for the treatment of SCLC in the future.

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Section: Discussionmentioning

confidence: 99%

Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF‑1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase‑3 signaling pathway in small cell lung cancer

Jiang

Meng

et al. 2018

Oncol Lett

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“…The traditional cancer prognosis pathway related UDP‐glucuronosyl transferase (UGT) 2B enzymes are important in the detoxification of a variety of endogenous and exogenous compounds, including many hormones, drugs, and carcinogens 58 . It has been reported that active function of AKR1C1 as a key component of the STAT3 pathway may promote lung cancer metastasis 59,60 . MGST2, the member of MGST family, primarily metabolizes foreign chemicals, such as drugs and environmental pollutants, and also plays roles in the detoxification of reactive compounds 61 .…”

Section: Discussionmentioning

confidence: 99%

“…58 It has been reported that active function of AKR1C1 as a key component of the STAT3 pathway may promote lung cancer metastasis. 59,60 MGST2, the member of MGST family, primarily metabolizes foreign chemicals, such as drugs and environmental pollutants, and also plays roles in the detoxification of reactive compounds. 61 These data suggest that UGT2B/AKR1C1/MGST2 variants are potential predictive biomarkers for cetuximab resistance.…”

Section: Discussionmentioning

confidence: 99%

New genetic variations discovered in KRAS wild‐type cetuximab resistant chinese colorectal cancer patients

Jing

Wang

et al. 2020

Molecular Carcinogenesis

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To perform a comprehensive genomic analysis of colorectal cancer (CRC) tumor to detect genetic variants and identify novel resistant mutations associated with cetuximab‐resistance in CRC patients. A retrospective study was performed using whole exome sequencing (WES) to identify common genetic factors from 22 cetuximab‐sensitive and 10 cetuximab‐resistant patients. In all 10 cetuximab‐resistant patients, we discovered there are 37 significantly mutated genes (SMGs). CYP4A11 was the most frequently mutated gene in cetuximab‐resistant patients. BCAS1 and GOLGA6L1 were found to be among the second group of frequently mutated genes with a frequency of 60%. After cosine similarity analysis, three mutational signatures (signature a, b, and c) were found in all CRC tumors, similar to signature 1, 5, and 6 in COSMIC, respectively. Gene ontology analysis was performed on SMGs and found 12 enriched GO terms. Four genes are enriched in six specific Kyoto Encyclopedia of Genes and Genomes pathway groups, including the metabolism of xenobiotics by cytochrome P450, steroid hormone biosynthesis, retinol metabolism, and drug metabolism. Our data supports a network composed of SMGs and cellular signaling pathways that have been positively linked to the mechanisms of cetuximab resistance. These involve DNA damage repair, angiogenesis, invasion, drug metabolism, and the CRC tumor microenvironment. There is a SMG, OR9G1 correlated with survival rates of KRAS wild‐type colon adenocarcinoma patients. These findings support further investigation using WES in a prospective clinical study of cetuximab resistance CRC, to further identify, confirm, and extend the clinical significance of these and other potentially important new candidate predictive biomarkers of cetuximab response.

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“…S1D). There are many well-documented pro-oncogenic genes (Kojima et al, 2019;Tian et al, 2016;Wu et al, 2019) that are upregulated upon the expression of EN2, implying that EN2 could modulate the expression of the downstream targets genes in a cellular, context-dependent manner. The upregulated oncogenic gene was investigated for its role in mediating the biological function of EN2 using SPARC in the Eca109 cell line.…”

Section: En2 Upregulates the Expression Of Sparcmentioning

confidence: 99%

Engrailed-2 promotes a malignant phenotype of esophageal squamous cell carcinoma through upregulating the expression of pro-oncogenic genes

Cao

Wang

Tang

et al. 2020

PeerJ

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Background A number of homeobox genes have been implicated in the development of various cancers. However, the role of engrailed 2 (EN2), a member of the homeobox gene superfamily, in esophageal squamous cell carcinoma (ESCC) remains unknown. Methods The expression of EN2 was examined using quantitative real-time PCR and immunohistochemistry. A stable cell line was established to express exogenous EN2 using a lentivirus system. The malignant phenotype was analyzed with proliferation, clonogenicity, wound-healing and invasion assays. The CRISPR/Cas9 system was adopted to deplete endogenous EN2. RNA profiling was performed using gene expression microarray. The ShRNA-mediated method was used to knock down the expression of SPARC. The structure-function relationship was determined using site-directed mutagenesis. Results EN2 is highly expressed in ESCC. The malignant phenotype of the ESCC cell line was amplified by an overexpression of EN2 but was attenuated by a disruption of EN2. RNA profiling analysis revealed that distinct sets of genes were modulated by the expression of EN2 in various ESCC cell lines and oncogenes were among these. EN2 greatly increased the expression of SPARC in Eca109. Site-directed mutagenesis revealed that the induction of SPARC was closely correlated with the protumor function of EN2. ShRNA-mediated knockdown of SPARC attenuated the malignant phenotype of EN2-infected cells. These data suggest that SPARC is crucial for mediating the protumor function of EN2. Discussion EN2 has an oncogenic function in ESCC that is mediated by upregulating the expression of pro-oncogenic genes downstream. EN2 may potentially act as a diagnostic marker or therapeutic target for ESCC treatment in the future.

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High expression of AKR1C1 is associated with proliferation and migration of small-cell lung cancer cells

Cited by 31 publications

References 34 publications

Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF‑1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase‑3 signaling pathway in small cell lung cancer

Wentilactone A induces cell apoptosis by targeting AKR1C1 gene via the IGF‑1R/IRS1/PI3K/AKT/Nrf2/FLIP/Caspase‑3 signaling pathway in small cell lung cancer

New genetic variations discovered in KRAS wild‐type cetuximab resistant chinese colorectal cancer patients

Engrailed-2 promotes a malignant phenotype of esophageal squamous cell carcinoma through upregulating the expression of pro-oncogenic genes

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