Cancer Research and Treatment

Original Articles

NFATC3–PLA2G15 Fusion Transcript Identified by RNA Sequencing Promotes Tumor Invasion and Proliferation in Colorectal Cancer Cell Lines: Jee-Eun Jang, Hwang-Phill Kim, Sae-Won Han, Hoon Jang, Si-Hyun Lee, Sang-Hyun Song, Duhee Bang, Tae-You Kim; Cancer Res Treat. 2019;51(1):391-401. Published online June 14, 2018; DOI: https://doi.org/10.4143/crt.2018.103

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Purpose
This study was designed to identify novel fusion transcripts (FTs) and their functional significance in colorectal cancer (CRC) lines.
Materials and Methods
We performed paired-end RNA sequencing of 28 CRC cell lines. FT candidates were identified using TopHat-fusion, ChimeraScan, and FusionMap tools and further experimental validation was conducted through reverse transcription-polymerase chain reaction and Sanger sequencing. FT was depleted in human CRC line and the effects on cell proliferation, cell migration, and cell invasion were analyzed.
Results
One thousand three hundred eighty FT candidates were detected through bioinformatics filtering. We selected six candidate FTs, including four inter-chromosomal and two intrachromosomal FTs and each FT was found in at least one of the 28 cell lines. Moreover, when we tested 19 pairs of CRC tumor and adjacent normal tissue samples, NFATC3–PLA2G15 FT was found in two. Knockdown of NFATC3–PLA2G15 using siRNA reduced mRNA expression of epithelial–mesenchymal transition (EMT) markers such as vimentin, twist, and fibronectin and increased mesenchymal–epithelial transition markers of E-cadherin, claudin-1, and FOXC2 in colo-320 cell line harboring NFATC3–PLA2G15 FT. The NFATC3–PLA2G15 knockdown also inhibited invasion, colony formation capacity, and cell proliferation.
Conclusion
These results suggest that that NFATC3–PLA2G15 FTs may contribute to tumor progression by enhancing invasion by EMT and proliferation.

Citations

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Whole transcriptome analysis identifies ALB-EEF1A1 fusion as a novel biomarker in metastatic colorectal cancer
Deeksha Rikhari, Ankit Srivastava, Sandhya Rai, Mubashra, Srinivas Patnaik, Sameer Srivastava
Cancer Pathogenesis and Therapy.2025;[Epub] CrossRef
Mediator regulates transcriptional termination through crosstalk with pre-mRNA 3′ end processing factors
Chengjiang Lu, Xue Bai, Hanqing Zhang, Yiyang Zhang, Ming Yang, Yuanming Zheng, Zhaohui Jin, Wancheng Yang, Gaoxing Guo, Qiang Huang, Ying Huang, Ligang Wu, Xiang-Dong Fu, Zhihua Zhang, Gang Wang
Molecular Cell.2025; 85(11): 2147. CrossRef
Nuclear Factor of Activated T Cells (NFAT) Proteins as Targeted Molecules in Diseases: A Narrative Review
Mohadese Mozafari, Siti Nurnasihah Md Hashim, Khairul Bariah Ahmad Amin Noordin, Siti Aishah Zainal, Ahmad Azlina
Cureus.2024;[Epub] CrossRef
Identification of predictive markers in the cerebrospinal fluid of patients with glioblastoma
N. E. Arnotskaya, T. I. Kushnir, I. A. Kudryavtsev, A. A. Mitrofanov, A. Kh. Bekyashev, V. E. Shevchenko
Advances in Molecular Oncology.2023; 10(2): 117. CrossRef
Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function
Charbel Akkawi, Jerome Feuillard, Felipe Leon Diaz, Khalid Belkhir, Nelly Godefroy, Jean-Marie Peloponese, Marylene Mougel, Sebastien Laine
Retrovirology.2023;[Epub] CrossRef
Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing
Sungbin An, Hyun Hee Koh, Eun Sol Chang, Juyoung Choi, Ji-Young Song, Mi-Sook Lee, Yoon-La Choi
Frontiers in Oncology.2022;[Epub] CrossRef
Multi-Omics Approaches in Colorectal Cancer Screening and Diagnosis, Recent Updates and Future Perspectives
Ihsan Ullah, Le Yang, Feng-Ting Yin, Ye Sun, Xing-Hua Li, Jing Li, Xi-Jun Wang
Cancers.2022; 14(22): 5545. CrossRef
Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer
Meng-Yuan Wang, Man Huang, Chao-Yi Wang, Xiao-Ying Tang, Jian-Gen Wang, Yong-De Yang, Xin Xiong, Chao-Wei Gao
Frontiers in Oncology.2021;[Epub] CrossRef
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Davide Maspero, Alice Dassano, Giulia Pintarelli, Sara Noci, Loris De Cecco, Matteo Incarbone, Davide Tosi, Luigi Santambrogio, Tommaso A Dragani, Francesca Colombo
Carcinogenesis.2020; 41(7): 918. CrossRef
Blocking NFATc3 ameliorates azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer in mice via the inhibition of inflammatory responses and epithelial-mesenchymal transition
Yan Lin, Moussa Harouna Koumba, Suxuan Qu, Dongxu Wang, Lianjie Lin
Cellular Signalling.2020; 74: 109707. CrossRef
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Nishu Dalal, Rekha Jalandra, Minakshi Sharma, Hridayesh Prakash, Govind K. Makharia, Pratima R. Solanki, Rajeev Singh, Anil Kumar
Biomedicine & Pharmacotherapy.2020; 131: 110648. CrossRef
Fusion Transcripts of Adjacent Genes: New Insights into the World of Human Complex Transcripts in Cancer
Vincenza Barresi, Ilaria Cosentini, Chiara Scuderi, Salvatore Napoli, Virginia Di Bella, Giorgia Spampinato, Daniele Filippo Condorelli
International Journal of Molecular Sciences.2019; 20(21): 5252. CrossRef
The Landscape of Actionable Gene Fusions in Colorectal Cancer
Filippo Pagani, Giovanni Randon, Vincenzo Guarini, Alessandra Raimondi, Michele Prisciandaro, Riccardo Lobefaro, Maria Di Bartolomeo, Gabriella Sozzi, Filippo de Braud, Patrizia Gasparini, Filippo Pietrantonio
International Journal of Molecular Sciences.2019; 20(21): 5319. CrossRef
Exploring disease-specific methylated CpGs in human male genital abnormalities by using methylated-site display-amplified fragment length polymorphism (MSD-AFLP)
Toshiki AIBA, Toshiyuki SAITO, Akiko HAYASHI, Shinji SATO, Harunobu YUNOKAWA, Maki FUKAMI, Yutaro HAYASHI, Kentaro MIZUNO, Yuichi SATO, Yoshiyuki KOJIMA, Seiichiroh OHSAKO
Journal of Reproduction and Development.2019; 65(6): 491. CrossRef

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Identification of Diverse Adenosine-to-Inosine RNA Editing Subtypes in Colorectal Cancer: Si-Hyun Lee, Hwang-Phill Kim, Jun-Kyu Kang, Sang-Hyun Song, Sae-Won Han, Tae-You Kim; Cancer Res Treat. 2017;49(4):1077-1087. Published online January 25, 2017; DOI: https://doi.org/10.4143/crt.2016.301

Abstract PDF Supplementary Material PubReader ePub

Purpose
RNA editing generates protein diversity by altering RNA sequences in coding regions without changing the overall DNA sequence. Adenosine-to-inosine (A-to-I) RNA editing events have recently been reported in some types of cancer, but they are rare in human colorectal cancer (CRC). Therefore, this study was conducted to identify diverse RNA editing in CRC.
Materials and Methods
We compared transcriptome data of 39 CRC samples and paired adjacent tissues from The Cancer Genome Atlas database to identify RNA editing patterns in CRC, focusing on canonical A-to-I RNA edits in coding sequence regions. We investigated nonsynonymous RNA editing patterns by comparing tumor and normal tissue transcriptome data.
Results
The number of RNA edits varied from 12 to 42 per sample. We also observed that hypoand hyper-RNA editing patterns were distinguishable within the samples. We found 10 recurrent nonsynonymous RNA editing candidates in nine genes (PDLIM, NEIL1, SRP9, GLI1, APMAP, IGFBP7, ZNF358, COPA, and ZNF587B) and validated some by Sanger sequencing and the inosine chemical erasing assay. We further showed that editing at these positions was performed by the adenosine deaminase acting on RNA 1 enzyme. Most of these genes are hypoedited in CRC, but editing of GLI1 was increased in cancer tissues compared with normal tissues.
Conclusion
Our results show that nonsynonymous RNA editing patterns can be used to identify CRC patients and could serve as novel biomarkers for CRC.

Citations

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Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis
Phaik Ju Teoh, Omer An, Tae-Hoon Chung, Jing Yuan Chooi, Sabrina H. M. Toh, Shuangyi Fan, Wilson Wang, Bryan T. H. Koh, Melissa J. Fullwood, Melissa G. Ooi, Sanjay de Mel, Cinnie Y. Soekojo, Leilei Chen, Siok Bian Ng, Henry Yang, Wee Joo Chng
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Cytokine.2018; 104: 30. CrossRef

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Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis: Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2017;49(3):643-655. Published online October 6, 2016; DOI: https://doi.org/10.4143/crt.2016.168

Abstract PDF Supplementary Material PubReader ePub

Purpose
KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo.
Materials and Methods
The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects.
Results
KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho- Src and proliferative-signaling molecules were down-regulated in KX-01–sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01– induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01–sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model.
Conclusion
KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

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Aberrant Epigenetic Modifications of LPHN2 Function as a Potential Cisplatin-Specific Biomarker for Human Gastrointestinal Cancer: Mi-Seong Jeon, Sang-Hyun Song, Jiyeon Yun, Jee-Youn Kang, Hwang-Phill Kim, Sae-Won Han, Tae-You Kim; Cancer Res Treat. 2016;48(2):676-686. Published online September 22, 2015; DOI: https://doi.org/10.4143/crt.2015.153

Abstract PDF PubReader ePub

Purpose
Epigenetic alterations of specific genes have recently been identified as diagnostic biomarkers for human cancers. However, there are currently no standardized epigenetic biomarkers for drug sensitivity in human gastrointestinal cancer. Therefore, the aim of this study is to identify a novel epigenetic biomarker in gastrointestinal cancer.
Materials and Methods
Using bisulfite sequencing and pyrosequencing analysis, DNA methylation patterns of gastric, colon primary tissues and their cancer cells were analyzed, and histone modifications were analyzed using chromatin immunoprecipitation assay. In addition, cancer cells were exposed to cisplatin and treated with a DNA methyltransferase inhibitor.
Results
We report that in human gastric and colon cancers, latrophilin 2 (LPHN2) is silenced by epigenetic modifications, including CpG island methylation and aberrant histone modifications. We also confirmed that LPHN2 was silenced by DNA hypermethylation in primary gastric and colon tumor tissues compared to their normal counterparts. Interestingly, we found that cancer cells with methylated LPHN2 showed higher sensitivity to cisplatin. Also, 5-aza- 2′-deoxycytidine combined with cisplatin decreased the cytotoxicity of cisplatin in cancer cells with methylated LPHN2. In addition, LPHN2 knockdown in cancer cells with high LPHN2 expression sensitized these cells to the anti-proliferative effects of cisplatin.
Conclusion
In human gastrointestinal cancer, we found that LPHN2 is regulated by epigenetic modifications, and that cancer cells with lower LPHN2 expression show higher sensitivity to cisplatin. Therefore, the methylation status of LPHN2 is a potential novel epigenetic biomarker for cisplatin treatment in human gastric and colon cancers.

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TGF-β Suppresses COX-2 Expression by Tristetraprolin-Mediated RNA Destabilization in A549 Human Lung Cancer Cells: Soyeong Kang, Ahrum Min, Seock-Ah Im, Sang-Hyun Song, Sang Gyun Kim, Hyun-Ah Kim, Hee-Jun Kim, Do-Youn Oh, Hyun-Soon Jong, Tae-You Kim, Yung-Jue Bang; Cancer Res Treat. 2015;47(1):101-109. Published online October 22, 2014; DOI: https://doi.org/10.4143/crt.2013.192

Abstract PDF PubReader ePub

Purpose
Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor β (TGF-β) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-β can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-β-responsive and overexpress COX-2.
Materials and Methods
Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-β. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference.
Results
We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-β. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-β, suggesting that TGF-β–induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-β rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-β. Furthermore, we showed that Smad3 is essential to TTP-dependent down-regulation of COX-2 expression in response to TGF-β.
Conclusion
The results of this study show that TGF-β down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells.

Citations

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