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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (3) : 330-343
Overexpressed long noncoding RNA CRNDE with distinct alternatively spliced isoforms in multiple cancers
Xuefei Ma1, Wei Zhang1,2, Rong Zhang3, Jingming Li1, Shufen Li1, Yunlin Ma1, Wen Jin1(), Kankan Wang1,2()
1. State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
3. Department of Hematology, Xi’an Gaoxin Hospital, Xi’an 710075, China
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Alternative splicing is a tightly regulated process that contributes to cancer development. CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers. However, whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear. In this study, we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies. The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner. Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies, including 3 reported and 8 unreported, and also implicated that the overexpressed isoforms differed in various cancer types. Furthermore, anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples, and even had different impacts on the expression of CRNDE isoforms. Finally, experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types. Collectively, our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms, and may provide promising targets for cancer diagnosis and therapy.

Keywords long noncoding RNA      CRNDE      alternative splicing     
Corresponding Authors: Wen Jin,Kankan Wang   
Just Accepted Date: 12 February 2018   Online First Date: 29 May 2018    Issue Date: 05 June 2019
 Cite this article:   
Xuefei Ma,Wei Zhang,Rong Zhang, et al. Overexpressed long noncoding RNA CRNDE with distinct alternatively spliced isoforms in multiple cancers[J]. Front. Med., 2019, 13(3): 330-343.
Cancer type Cancer name GEO (No.) Cancer samples (No.) Control samples (No.) Ref.
Solid tumors CRC GSE32323 CRC tissues (17) Normal colorectal tissuesb (17) [27]
GSE8671 Colorectal adenoma (32) Normal colorectal mucosab (32) [28]
GSE37364 CRC tissues (14) Normal colonic mucosa (38) [29]
GSE4183 CRC and adenoma (30) Normal controls (8) [30]
Glioma GSE4290 Glioma samples (157) Non-tumor samples (23) [31]
ACC GSE19750 ACC samples (44) Normal adrenal glands (4) [32]
GSE10927 ACC samples (33) Normal adrenal cortex (10) [33]
Pancreatic cancer GSE16515 Pancreatic tumor (36) Normal pancreatic tissues (16) [34]
GSE22780 Pancreatic tumor (8) Normal tissuesb (8) [35]
GSE15471 PDAC samples (36) Normal tissuesb (36) [36]
Prostate cancer GSE55945 Prostate cancer (12) Normal tissues (7) [37]
GSE46602 Prostate cancer (36) Normal prostate (14) [38]
Ovarian cancer GSE14407 CEPI samples (12) Normal OSE (12) [39]
Cervical cancer GSE63514 Cervical cancer (28) Normal cervical epithelium (24) [40]
NSCLC GSE33532 NSCLC tissues (80) Normal lung tissues (20) [41]
NMSC GSE53462a NMSC tissues (21) Normal skin tissues (5) [42]
Leukemia ATL GSE1466 ATL samples (41) Normal T cells (3) [43]
AML GSE12662 AML samples (76) Normal PMN (5) [44]
GSE13159 AML samples (542) Healthy BM (74) [45,46]
CML GSE13159 CML samples (76) Healthy BM (74) [45,46]
ALL GSE13159 ALL samples (750) Healthy BM (74) [45,46]
MDS GSE13159 MDS samples (206) Healthy BM (74) [45,46]
CLL GSE13159 CLL samples (448) Healthy BM (74) [45,46]
GSE67642a CLL-CD19+ cells (15) Normal CD19+ cells (9) [47]
GSE50006 CLL cells (188) Normal B cells (32) NAc
Total 15 types 21 data sets 2938 397
Tab.1  GEO data sets used to detect CRNDE expression in 15 types of cancers
Fig.1  Alternatively spliced variants derived from the CRNDE locus. The CRNDE genomic locus (on the reverse strand) and its 12 transcript variants are pictured. The blue boxes and black dotted lines represent exons and introns, respectively. The target regions by Illumina HumanHT-12 V4.0 (ILMN_3250268 and ILMN_3240698) and Affymetrix HG-U133 (238021_s_at and 238022_at) probes are shown on top of the schematic diagram. The sequence gap in CRNDE-f is the unknown sequence region.
Fig.2  The tissue-specific expression pattern of CRNDE in various normal human tissues. The expression data of CRNDE in 109 types of normal tissues are from the Body Atlas, Tissues, at The unassayed tissues have been omitted. The median expression level of total tissue types is shown with the blue line. # stands for the expression value of 16 700 in testes and * stands for 6020 in the parotid gland. The data are presented as mean±standard deviation.
Fig.3  Cancer-specific expression patterns of CRNDE in solid tumors. Sixteen microarray data sets were analyzed, encompassing nine types of solid tumors with 596 tumor samples and 274 corresponding normal or adjacent noncancerous controls. The signal intensities of CRNDE detected by 238021_s_at probe are presented by scatter plots in CRC (A), glioma (B), ACC (C), pancreatic tumor (D), prostate cancer (E), ovarian cancer (G), cervical cancer (H), and NSCLC (I). The signal intensity of CRNDE in NMSC was detected by ILMN_3250268 probe (F). The detailed information of the examined data sets can be found in Table 1. Paired or unpaired t-test was performed to analyze significant differences (* P<0.05, ** P<0.01).
Fig.4  Highly expressed CRNDE in the majority of hematopoietic cancers. (A) The microarray data (GSE13159) included 5 types of leukemia encompassing 2022 leukemia samples and 74 corresponding normal controls. The signal intensities of CRNDE expression are shown by scatter plots and detected by 238021_s_at (upper panel) and 238022_at (lower panel) probes. The x-axis represents the five types of indicated leukemia. (B) The expression levels of CRNDE in ATL patient samples were compared with normal CD4-positive T cells by 238021_s_at (upper panel) and 238022_at (lower panel) probes. Unpaired t-test was performed to analyze significant differences (* P<0.05, ** P<0.01).
Fig.5  Repression of overexpressed CRNDE by anti-cancer drugs in cancer cell lines and patient samples. (A) The signal intensities of CRNDE expression levels were detected by two Affymetrix HG-U133 probes, 238021_s_at and 238022_at, in HCT116 cells (GSE15395), DU145 cells (GSE15392), and PBMC cells (GSE15389). (B and C) The relative intensities of CRNDE expression were detected by 238021_s_at and 238022_at probes in HCT116 (B) and DU154 (C) before and after R547 treatment, respectively [23]. (D) CRNDE expression was detected by ILMN_3250268 probe in macrophages and AML-M5 cell line THP1 with PMA treatment (GSE46599) [24]. (E) The signal intensities of CRNDE were detected by 238021_s_at and 238022_at probes in normal bone marrow samples and CML patient samples before and after imatinib therapy, respectively (GSE33075) [25]. Paired or unpaired t-test was performed to analyze significant differences (* P<0.05, ** P<0.01).
Fig.6  Experimental evidence illustrating the detailed expression patterns of 12 alternatively spliced isoforms of CRNDE in eight types of cancer cell lines. (A) The schematic diagram shows the CRNDE transcripts and fragments amplified by isoform-specific primer pairs. The blue and orange arrows represent exons and retained introns, respectively. The amplified fragments are marked with bidirectional red arrows. Unique sequences for discriminating each isoform are listed above the corresponding isoforms. (B) RT-PCR assays were performed to detect each isoform of CRNDE by corresponding specific primers. In addition, the amplified fragments were visualized by electrophoresis on agarose gels. (C–J) The relative expression of 12 CRNDE isoforms were determined by qRT-PCR assays in CRC cell lines HT29 (C) and HCT116 cells (D), glioma cancer cell lines U251 (E) and U87MG cells (F), AML cell lines Kasumi-1 (G), U937 (H) and THP1 cells (I), and CML cell line K562 cells (J). The x-axis represents 12 isoforms of CRNDE by letters. The y-axis shows the mean 2−ΔCt values from three independent experiments, and error bars represent the standard deviation.
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