Abstract
Background
Aberrant expressions of long non-coding RNAs promote cancer development including colorectal cancer. Expression profiling of cancer-related lncRNAs may introduce new deregulated lncRNAs that might be recruited as novel platforms in diagnosis and therapy of CRC.
Methods and Results
In this study, we exploited the SBI Human LncProfiler qPCR Array to examine the expression pattern of 90 cancer-related lncRNAs in CRC samples. Among deregulated lncRNAs, HAR1B, JPX, and KRASP1- which were showed a significantly higher expression profile in aggressive CRC tumors- were selected for more validation. We found that HAR1B and JPX expression profiles may discriminate between adjacent, adenomatous colorectal polyps, and colorectal cancer samples. The area under the curve of near 0.7 and a sensitivity/specificity of more than 70.80%, respectively, claim a suitable cancer prognostic potential for these two lncRNAs, JPX and HAR1B. Further analysis revealed that HAR1B and JPX may contribute to CRC pathobiology through affecting the FOXO, ErbB, and Wnt/β-catenin signaling pathways.
Conclusions
Upregulated JPX and HAR1B lncRNAs may contribute to colorectal cancer pathobiology by affecting multiple cancer-related signaling pathways. They also potentially discriminate between CRC tumors, marginals, and adenomatous colorectal polyps.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11033-022-07396-z/MediaObjects/11033_2022_7396_Fig1_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11033-022-07396-z/MediaObjects/11033_2022_7396_Fig2_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11033-022-07396-z/MediaObjects/11033_2022_7396_Fig3_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11033-022-07396-z/MediaObjects/11033_2022_7396_Fig4_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11033-022-07396-z/MediaObjects/11033_2022_7396_Fig5_HTML.png)
Similar content being viewed by others
References
Siddiqui H, Al-Ghafari A, Choudhry H, Al Doghaither H (2019) Roles of long non-coding RNAs in colorectal cancer tumorigenesis: A Review. Mol Clin Oncol 11(2):167–172. DOI: https://doi.org/10.3892/mco.2019.1872
Neve B, Jonckheere N, Vincent A, Van Seuningen I (2018) Epigenetic regulation by lncRNAs: an overview focused on UCA1 in colorectal cancer. Cancers 10(11):440. DOI: https://doi.org/10.3390/cancers10110440
Yang X, Duan B, Zhou X (2017) Long non-coding RNA FOXD2-AS1 functions as a tumor promoter in colorectal cancer by regulating EMT and Notch signaling pathway. Eur Rev Med Pharmacol Sci 21(16):3586–3591
Forrest ME, Saiakhova A, Beard L, Buchner DA, Scacheri PC, LaFramboise T, Markowitz S, Khalil AM (2018) Colon Cancer-upregulated Long non-coding RNA lincDUSP regulates cell cycle genes and potentiates resistance to apoptosis. Sci Rep 8(1):1–12. DOI: https://doi.org/10.1038/s41598-018-25530-5
Khajehdehi M, Khalaj-Kondori M, Ghasemi T, Jahanghiri B, Damaghi M (2021) Long Noncoding RNAs in Gastrointestinal Cancer: Tumor Suppression Versus Tumor Promotion. Dig Dis Sci 66(2):381–397. DOI: https://doi.org/10.1007/s10620-020-06200-x
Ghasemi T, Khalaj-Kondori M, Hosseinpour Feizi MA, Asadi P (2020) lncRNA-miRNA-mRNA interaction network for colorectal cancer; An in silico analysis. Comput Biol Chem 89:107370. DOI: https://doi.org/10.1016/j.compbiolchem.2020.107370
Shan Y, Ma J, Pan Y, Hu J, Liu B, Jia L (2018) LncRNA SNHG7 sponges miR-216b to promote proliferation and liver metastasis of colorectal cancer through upregulating GALNT1. Cell Death Dis 9(7):1–13. DOI: https://doi.org/10.1038/s41419-018-0759-7
Liu B, Pan S, Xiao Y, Liu Q, Xu J, Jia L (2018) LINC01296/miR-26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway. J Experimental Clin Cancer Res 37(1):1–15. DOI: https://doi.org/10.1186/s13046-018-0994-x
Jahangiri B, Khalaj-Kondori M, Asadollahi E, Sadeghizadeh M (2019) Cancer-associated fibroblasts enhance cell proliferation and metastasis of colorectal cancer SW480 cells by provoking long noncoding RNA UCA1. J Cell Commun Signal 13(1):53–64. DOI: https://doi.org/10.1007/s12079-018-0471-5
Luo J, Qu J, Wu D-K, Lu Z-L, Sun Y-S, Qu Q (2017) Long non-coding RNAs: a rising biotarget in colorectal cancer. Oncotarget 8(13):22187. DOI: https://doi.org/10.18632/oncotarget.14728
Bai Z, Wang J, Wang T, Li Y, Zhao X, Wu G, Yang Y, Deng W, Zhang Z (2017) The MiR-495/Annexin A3/P53 axis inhibits the invasion and EMT of colorectal cancer cells. Cell Physiol Biochem 44(5):1882–1895. DOI: https://doi.org/10.1159/000485877
Slaby O (2016) Non-coding RNAs as biomarkers for colorectal cancer screening and early detection. Adv Exp Med Biol 937:153–170. DOI: https://doi.org/10.1007/978-3-319-42059-2_8
Shen J, Siegel AB, Remotti H, Wang Q, Shen Y, Santella RM (2015) Exploration of deregulated long non-coding RNAs in association with hepatocarcinogenesis and survival. Cancers 7(3):1847–1862. DOI: https://doi.org/10.3390/cancers7030865
Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X (2020) lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol Cancer 19(1):1–17. DOI: https://doi.org/10.1186/s12943-020-1133-9
Jin M, Ren J, Luo M, You Z, Fang Y, Han Y, Li G, Liu H (2020) Long non-coding RNA JPX correlates with poor prognosis and tumor progression in non-small-cell lung cancer by interacting with miR-145-5p and CCND2. Carcinogenesis 41(5):634–645. DOI: https://doi.org/10.1093/carcin/bgz125
Lin X-q, Huang Z-m, Chen X, Wu F, Wu W (2018) XIST induced by JPX suppresses hepatocellular carcinoma by sponging miR-155-5p. Yonsei Med J 59(7):816–826. DOI: https://doi.org/10.3349/ymj.2018.59.7.816
Ma W, Wang H, Jing W, Zhou F, Chang L, Hong Z, Liu H, Liu Z, Yuan Y (2017) Downregulation of long non-coding RNAs JPX and XIST is associated with the prognosis of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 41(2):163–170. DOI: https://doi.org/10.1016/j.clinre.2016.09.002
Guglas K, Kolenda T, Teresiak A, Kopczyńska M, Łasińska I, Mackiewicz J, Mackiewicz A, Lamperska K (2018) lncRNA expression after irradiation and chemoexposure of HNSCC cell lines. Non-coding RNA 4(4):33. DOI: https://doi.org/10.3390/ncrna4040033
Morotti A, Verdelli C, Guarnieri V, Muscarella LA, Silipigni R, Guerneri S, Vicentini L, Vaira V (2019) Corbetta. Menin and EZH2 activities modulate the expression of the long non-coding RNA HAR1B in parathyroid tumors. 21st European Congress of Endocrinology. BioScientifica
Liu H, Ye T, Yang X, Lv P, Wu X, Zhou H, Zeng J, Tang K, Ye Z (2020) A Panel of Four-lncRNA Signature as a Potential Biomarker for Predicting Survival in Clear Cell Renal Cell Carcinoma. J Cancer 11(14):4274. DOI: https://doi.org/10.7150/jca.40421
Mullany LE, Slattery ML (2019) The functional role of miRNAs in colorectal cancer: insights from a large population-based study. Cancer biology & medicine 16(2):211. DOI: https://doi.org/10.20892/j.issn.2095-3941.2018.0514
Dai W, Mu L, Cui Y, Li Y, Chen P, Xie H, Wang X (2019) Long noncoding RNA CASC2 enhances berberineinduced cytotoxicity in colorectal cancer cells by silencing BCL2. Mol Med Rep 20(2):995–1006. DOI: https://doi.org/10.3892/mmr.2019.10326
Liang Y, Song X, Li Y, Chen B, Zhao W, Wang L, Zhang H, Liu Y, Han D, Zhang N (2020) LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer 19:1–20. DOI: https://doi.org/10.1186/s12943-020-01206-5
Rahmoon MA, Youness RA, Gomaa AI, Hamza MT, Waked I, El Tayebi HM, Abdelaziz AI (2017) MiR-615-5p depresses natural killer cells cytotoxicity through repressing IGF-1R in hepatocellular carcinoma patients. Growth Factors 35(2–3):76–87. DOI: https://doi.org/10.1080/08977194.2017.1354859
Gao Y, Zhang S, Wang Z, Liao J (2017) Down-regulation of miR-342-3p in hepatocellular carcinoma tissues and its prognostic significance. Eur Rev Med Pharmacol Sci 21(9):2098–2102
Wei H, Hu J, Pu J, Tang Q, Li W, Ma R, Xu Z, Tan C, Yao T, Wu X (2019) Long noncoding RNA HAGLROS promotes cell proliferation, inhibits apoptosis and enhances autophagy via regulating miR-5095/ATG12 axis in hepatocellular carcinoma cells. Int Immunopharmacol 73:72–80. DOI: https://doi.org/10.1016/j.intimp.2019.04.049
Dou G-x, Zhang J-n, Wang P, Wang J-l, Sun G-b (2019) Long Intergenic Non-Protein-Coding RNA 01138 Accelerates Tumor Growth and Invasion in Gastric Cancer by Regulating miR-1273e. Med Sci monitor: Int Med J experimental Clin Res 25:2141. DOI: https://doi.org/10.12659/MSM.914248
Yin G, Tian P, BuHe A, Yan W, Li T, Sun Z (2020) LncRNA LINC00689 Promotes the Progression of Gastric Cancer Through Upregulation of ADAM9 by Sponging miR-526b-3p. Cancer Manage Res 12:4227–4239
Zhang PF, Wu J, Wu Y, Huang W, Liu M, Dong ZR, Xu BY, Jin Y, Wang F, Zhang XM (2019) The lncRNA SCARNA2 mediates colorectal cancer chemoresistance through a conserved microRNA-342‐3p target sequence. J Cell Physiol 234(7):10157–10165
Yan Y, Zhang D, Lei T, Zhao C, Han J, Cui J, Wang Y (2019) MicroRNA-33a-5p suppresses colorectal cancer cell growth by inhibiting MTHFD2. Clin Exp Pharmacol Physiol 46(10):928–936. DOI: https://doi.org/10.1111/1440-1681.13125
Tang JT, Zhao J, Sheng W, Zhou JP, Dong Q, Dong M (2019) Ectopic expression of miR-944 impairs colorectal cancer cell proliferation and invasion by targeting GATA binding protein 6. J Cell Mol Med 23(5):3483–3494. DOI: https://doi.org/10.1111/jcmm.14245
Lou C, Zhao J, Gu Y, Li Q, Tang S, Wu Y, Tang J, Zhang C, Li Z, Zhang Y (2020) LINC01559 accelerates pancreatic cancer cell proliferation and migration through YAP-mediated pathway. J Cell Physiol 235(4):3928–3938. DOI: https://doi.org/10.1002/jcp.29288
Ma T, Chen H, Wang P, Yang N, Bao J (2020) Downregulation of lncRNA ZEB1-AS1 Represses Cell Proliferation, Migration, and Invasion Through Mediating PI3K/AKT/mTOR Signaling by miR-342-3p/CUL4B Axis in Prostate Cancer. Cancer Biother Radiopharm. DOI: https://doi.org/10.1089/cbr.2019.3123
Peng X, Gao J, Cai C, Zhang Y (2020) LncRNA LINC01503 aggravates the progression of cervical cancer through sponging miR-342-3p to mediate FXYD3 expression. Biosci Rep 40(6). DOI: https://doi.org/10.1042/BSR20193371
Guan X, Zong Z-h, Liu Y, Chen S, Wang L-l, Zhao Y (2019) circPUM1 promotes tumorigenesis and progression of ovarian cancer by sponging miR-615-5p and miR-6753-5p. Mol Therapy-Nucleic Acids 18:882–892. DOI: https://doi.org/10.1016/j.omtn.2019.09.032
Guan X, Guan Y (2020) miR-145-5p attenuates paclitaxel resistance and suppresses the progression in drug-resistant breast cancer cell lines. Neoplasma 67(5):972–981. DOI: https://doi.org/10.4149/neo_2020_190622N536
Hu X, Duan L, Liu H, Zhang L (2019) Long noncoding RNA LINC01296 induces non-small cell lung cancer growth and progression through sponging miR-5095. Am J translational Res 11(2):895
Pan J, Fang S, Tian H, Zhou C, Zhao X, Tian H, He J, Shen W, Meng X, Jin X, Gong Z (2020) lncRNA JPX/miR-33a-5p/Twist1 axis regulates tumorigenesis and metastasis of lung cancer by activating Wnt/β-catenin signaling. Mol Cancer 19(1):9. DOI: https://doi.org/10.1186/s12943-020-1133-9
Ren J, Yang Y, Xue J, Xi Z, Hu L, Pan S-J, Sun Q (2018) Long noncoding RNA SNHG7 promotes the progression and growth of glioblastoma via inhibition of miR-5095. Biochem Biophys Res Commun 496(2):712–718. DOI: https://doi.org/10.1016/j.bbrc.2018.01.109
Chen J, Chen T, Zhu Y, Li Y, Zhang Y, Wang Y, Li X, Xie X, Wang J, Huang M, Sun X, Ke Y (2019) circPTN sponges miR-145-5p/miR-330-5p to promote proliferation and stemness in glioma. J Exp Clin Cancer Res 38(1):398. DOI: https://doi.org/10.1186/s13046-019-1376-8
Song X, Jin Y, Yan M, Zhang Y, Chen B (2019) MicroRNA3423p functions as a tumor suppressor by targeting LIM and SH3 protein 1 in oral squamous cell carcinoma. Oncol Lett 17(1):688–696. DOI: https://doi.org/10.3892/ol.2018.9637
Lan X, Liu X, Sun J, Yuan Q, Li J (2019) CircRAD23B facilitates proliferation and invasion of esophageal cancer cells by sponging miR-5095. Biochem Biophys Res Commun 516(2):357–364. DOI: https://doi.org/10.1016/j.bbrc.2019.06.044
Farhan M, Wang H, Gaur U, Little PJ, Xu J, Zheng W (2017) FOXO Signaling Pathways as Therapeutic Targets in Cancer. Int J Biol Sci 13(7):815–827. DOI: https://doi.org/10.7150/ijbs.20052
Jiramongkol Y, Lam EW (2020) FOXO transcription factor family in cancer and metastasis. Cancer Metastasis Rev 39(3):681–709. DOI: https://doi.org/10.1007/s10555-020-09883-w
Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813(11):1978–1986. DOI: https://doi.org/10.1016/j.bbamcr.2011.03.010
Gajos-Michniewicz A, Czyz M (2020) WNT Signaling in Melanoma. Int J Mol Sci 21(14). DOI: https://doi.org/10.3390/ijms21144852
Cheng X, Xu X, Chen D, Zhao F, Wang W (2019) Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer. Biomed Pharmacother 110:473–481. DOI: https://doi.org/10.1016/j.biopha.2018.11.082
Wang Z (2017) ErbB Receptors and Cancer. Methods Mol Biol 1652:3–35. DOI: https://doi.org/10.1007/978-1-4939-7219-7_1
Zhao B, Wang L, Qiu H, Zhang M, Sun L, Peng P, Yu Q, Yuan X (2017) Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget 8(3):3980–4000. DOI: https://doi.org/10.18632/oncotarget.14012
Dong W, Cao Z, Pang Y, Feng T, Tian H (2019) CARF, As An Oncogene, Promotes Colorectal Cancer Stemness By Activating ERBB Signaling Pathway. Onco Targets Ther 12:9041–9051. DOI: https://doi.org/10.2147/ott.S225733
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
Khalaj, as the project administrator, prepared the resources and has played a key role in the planning and methodology of the project with the cooperation of Khajehdehi. Writing- Original draft preparation, Investigation, and Software and Formal analysis has been done by Khajehdehi. Khalaj and Hosseinpour feizi contributed to the Review & Editing of the writing.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there are no conflicts of interest.
Ethical approval
This study approved by the Ethics Committee of the University of Tabriz (IR.TABRIZU.REC.1398.027). It is also under the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Khajehdehi, M., Khalaj-Kondori, M. & Hosseinpour Feizi, M.A. Expression profiling of cancer-related long non-coding RNAs revealed upregulation and biomarker potential of HAR1B and JPX in colorectal cancer. Mol Biol Rep 49, 6075–6084 (2022). https://doi.org/10.1007/s11033-022-07396-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-022-07396-z