Journal of Shandong University (Health Sciences) ›› 2025, Vol. 63 ›› Issue (9): 108-115.doi: 10.6040/j.issn.1671-7554.0.2025.0357

• Clinical Research • Previous Articles    

The functional role and clinical significance of lncRNA HEATR3-AS1 in colorectal cancer tumorigenesis and progression

LI Ziqi1, WEI Yanruoxue1, LIU Xiaohan1, LIU Chuncheng1, ZHAO Ran1,2, LIU Yukun1,2   

  1. 1. Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China;
    2. Department of Pathology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong, China
  • Published:2025-09-08

PDF (PC)

120

Abstract: Objective To investigate the expression characteristics, subcellular localization, molecular functions, clinicopathological significance, and prognostic evaluation value of long non-coding RNA HEATR3-AS1 in colorectal cancer(CRC). Methods Quantitative real-time polymerase chain reaction(RT-qPCR)was used to detecte the expression level of HEATR3-AS1 in CRC tissues, and fluorescence in situ hybridization(FISH)was used to clarify its subcellular localization. The correlation between the expression of HEATR3-AS1 and HEATR3 mRNA was analyzed. The eukaryotic expression vector containing HEATR3-AS1 was constructed using molecular cloning techniques and the HEATR3-AS1-overexpressed cell model was constructed to elucidate the effect of its overexpression on HEATR3 mRNA expression. In situ hybridization(ISH)was employed to analyze the correlation of its expression in CRC tissues with clinicopathological features and poor prognosis in CRC patients. Results The expression of HEATR3-AS1 in CRC tissues demonstrated a marked upregulation compared with paracancerous normal tissues(P=0.019 2)and was explicitly localized in the nucleus of CRC cells. A significant positive correlation was observed between HEATR3-AS1 and HEATR3 mRNA expression levels(P=0.020 2), and its overexpression promoted the expression of HEATR3 mRNA(P=0.007 7). High expression of HEATR3-AS1 was significantly associated with advanced TNM stage(P=0.029)and lymph node metastasis(P=0.036). Survival curve analysis revealed that colorectal cancer patients with elevated HEATR3-AS1 expression experienced a marked reduction in overall survival(OS)compared to those with low expression(P=0.001 1). Multivariate Cox analysis confirmed that high expression of HEATR3-AS1 could serve as an independent poor prognostic factor in CRC patients(HR=3.355, 95%CI=1.632-7.193, P=0.001 3). Conclusion HEATR3-AS1 is overexpressed and specifically localized in the nucleus of CRC cells. Its overexpression may regulate the transcription of HEATR3, and its aberrantly high expression serves as an independent prognostic factor for colorectal cancer, highlighting its potential as a novel biomarker for molecular classification and survival prediction in CRC.

Key words: Colorectal cancer, lncRNA HEATR3 Antisense RNA 1, In situ hybridization, Fluorescence in situ hybridization, Prognosis

CLC Number: 

  • R735.3
[1] Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer[J]. Lancet, 2019, 394(10207): 1467-1480.
[2] Li Q, Geng S, Luo H, et al. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy[J]. Signal Transduct Target Ther, 2024, 9(1): 266. doi: 10.1038/s41392-024-01953-7
[3] Johdi NA, Sukor NF. Colorectal cancer immunotherapy: options and strategies[J]. Front Immunol, 2020, 11: 1624. doi: 10.3389/fimmu.2020.01624
[4] 魏闫若雪, 李梓绮, 刘春铖, 等. 结直肠癌中SP1的瘤内异质性表达及其临床意义[J]. 山东大学学报(医学版), 2024, 62(5): 89-94. WEI Yanruoxue, LI Ziqi, LIU Chuncheng, et al. Intratumor heterogeneity of SP1 expression in colorectal cancer and its clinical significance[J]. Journal of Shandong University(Health Sciences), 2024, 62(5): 89-94.
[5] Brody H. Colorectal cancer[J]. Nature, 2015, 521(7551): S1. doi:10.1038/521s1a
[6] Hussen BM, Sulaiman SHA, Abdullah SR, et al. MiRNA-155: a double-edged sword in colorectal cancer progression and drug resistance mechanisms[J]. Int J Biol Macromol, 2025, 299: 140134. doi:10.1016/j.ijbiomac.2025.140134
[7] Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics[J]. Trends Pharmacol Sci, 2023, 44(4): 222-236.
[8] Herman AB, Tsitsipatis D, Gorospe M. Integrated lncRNA function upon genomic and epigenomic regulation[J]. Mol Cell, 2022, 82(12): 2252-2266.
[9] Ali T, Grote P. Beyond the RNA-dependent function of LncRNA genes[J]. eLife, 2020, 9: e60583. doi:10.7554/elife.60583
[10] Lin XT, Zhuang SW, Chen X, et al. lncRNA ITGB8-AS1 functions as a CeRNA to promote colorectal cancer growth and migration through integrin-mediated focal adhesion signaling[J]. Mol Ther, 2022, 30(2): 688-702.
[11] Entezari M, Taheriazam A, Orouei S, et al. LncRNA-miRNA axis in tumor progression and therapy response: an emphasis on molecular interactions and therapeutic interventions[J]. Biomed Pharmacother, 2022, 154: 113609. doi:10.1016/j.biopha.2022.113609
[12] Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis[J]. Nature, 2010, 464(7291): 1071-1076.
[13] Gutschner T, Hömmerle M, Eissmann M, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells[J]. Cancer Res, 2013, 73(3): 1180-1189.
[14] Xu WW, Jin J, Wu XY, et al. MALAT1-related signaling pathways in colorectal cancer[J]. Cancer Cell Int, 2022, 22(1): 126. doi: 10.1186/s12935-022-02540-y
[15] ODonohue MF, Da Costa L, Lezzerini M, et al. HEATR3 variants impair nuclear import of uL18(RPL5)and drive Diamond-Blackfan Anemia[J]. Blood, 2022, 139(21): 3111-3126.
[16] Xiao S, Yu T, Yang F, et al. LMAN2 interacts with HEATR3 to expedite HER2-positive breast cancer advancement and inflammation and Akt/ERK/NF-κB signaling[J]. Biochem Cell Biol, 2025, 103: 1-11. doi:10.1139/bcb-2024-0166
[17] Hu C. LncRNA DSCAM-AS1: a pivotal therapeutic target in cancer[J]. Mini Rev Med Chem, 2023, 23(5): 530-536.
[18] Miao H, Wang L, Zhan H, et al. A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation[J]. PLoS Genet, 2019, 15(5): e1008144. doi:10.1371/journal.pgen.1008144
[19] Buranjiang G, Abuduwanke A, Li XW, et al. LncRNA HOTAIR enhances RCC2 to accelerate cervical cancer progression by sponging miR-331-3p[J]. Clin Transl Oncol, 2023, 25(6): 1650-1660.
[20] Pelagiadis I, Kyriakidis I, Katzilakis N, et al. The diverse genomic landscape of diamond-blackfan Anemia: two novel variants and a mini-review[J]. Children(Basel), 2023, 10(11): 1812. doi:10.3390/children10111812
[21] Zhang W, Hui KY, Gusev A, et al. Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3[J]. Genes Immun, 2013, 14(5): 310-316.
[22] Dou X, Ma XY, Meng WT, et al. HEATR3 involved in the cell proliferation, metastasis and cell cycle development of bladder cancer acts as a tumor suppressor[J]. Mol Genet Genom, 2023, 298(6): 1353-1364.
[23] Hashemi M, Moosavi MS, Abed HM, et al. Long non-coding RNA(lncRNA)H19 in human cancer: From proliferation and metastasis to therapy[J]. Pharmacol Res, 2022, 184: 106418. doi:10.1016/j.phrs.2022.106418
[24] Raju GSR, Pavitra E, Bandaru SS, et al. HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer[J]. Mol Cancer, 2023, 22(1): 65. doi:10.1186/s12943-023-01765-3
[25] Xu W, Ding M, Wang B, et al. Molecular mechanism of the canonical oncogenic lncRNA MALAT1 in gastric cancer[J]. Curr Med Chem, 2021, 28(42): 8800-8809.
[26] 甄全胜, 王立娟, 刘冬梅. 声门上型喉癌患者血清LncRNA MALAT1、miR-204-5p表达与预后的关系[J]. 中国耳鼻咽喉头颈外科, 2024, 31(11): 698-702. ZHEN Quansheng, WANG Lijuan, LIU Dongmei. Relationship between serum LncRNA MALAT1 and miR-204-5p expression and prognosis in patients with supraglottic carcinoma[J]. Chinese Archives of Otolaryngology-Head and Neck Surgery, 2024, 31(11): 698-702.
[27] 徐伟强, 章平. LncRNA MALAT1在胃癌组织中的表达及其与临床病理特征和预后关系的研究[J]. 哈尔滨医科大学学报, 2024, 58(4): 401-405. XU Weiqiang, ZHANG Ping. Expression of LncRNA MALAT1 in gastric cancer and its relationship with clinicopathological features and prognosis[J]. Journal of Harbin Medical University, 2024, 58(4): 401-405.
[28] 梁亚海, 李金媚, 彭晓霞, 等. 血清LncRNA MALAT1和microRNA-124水平检测对非小细胞肺癌患者预后的评估价值[J]. 现代肿瘤医学, 2024, 32(7): 1254-1259. LIANG Yahai, LI Jinmei, PENG Xiaoxia, et al. The prognostic value of serum LncRNA MALAT1and microRNA-124levels in non-small cell lung cancer patients[J]. Journal of Modern Oncology, 2024, 32(7): 1254-1259.
[29] 张建树, 张瀚文, 赵文静. 长链非编码RNA ZNF528-AS1促进乳腺癌他莫昔芬耐药及进展转移[J]. 山东大学学报(医学版), 2023, 61(1): 17-26. ZHANG Jianshu, ZHANG Hanwen, ZHAO Wenjing. LncRNA ZNF528-AS1 promotes tamoxifen resistance and progression of breast cancer[J]. Journal of Shandong University(Health Sciences), 2023, 61(1): 17-26.
[30] 孙永康, 颜学波, 朱泽民, 等. 长链非编码RNA MALAT1在肝细胞癌发生发展中的作用[J]. 临床肝胆病杂志, 2021, 37(3): 704-708. SUN Yongkang, YAN Xuebo, ZHU Zemin, et al. Role of long non-coding RNA MALAT1 in the development and progression of hepatocellular carcinoma[J]. Journal of Clinical Hepatology, 2021, 37(3): 704-708.
[31] 郭向阳, 苗立峰, 张国琛. 血清外泌体SUMO1P3和MALAT1对三阴性乳腺癌患者术后复发转移的预测价值[J]. 临床肿瘤学杂志, 2024, 29(6): 561-565. GUO Xiangyang, MIAO Lifeng, ZHANG Guochen. The predictive value of serum exosome SUMO1P3 and MALAT1 for postoperative recurrence and metastasis in patients with triple-negative breast cancer[J]. Chinese Clinical Oncology, 2024, 29(6): 561-565.
[1] LIU Baoguo, SONG Xiang, ZHAO Xiaowen, MAO Yali. Application value of serum STAT5B and NKAIN1 mRNA detection in breast cancer [J]. Journal of Shandong University (Health Sciences), 2025, 63(7): 68-74.
[2] WANG Lei, CHANG Xiao, WANG Zimeng, LI Jiaojiao, CUI Shujun, YANG Fei, ZHU Yuexiang. Predictive value of intratumoral and peritumoral DCE-MRI imaging histology for progression-free survival in patients with cervical cancer [J]. Journal of Shandong University (Health Sciences), 2025, 63(6): 45-54.
[3] JIA Ruoxi, LYU Li, LIU Hanyun, WU Yinping, LI Fengcai, ZHAO Zehua, WANG Kai, FAN Yuchen. Diagnostic value of blood cell count-related biomarkers in predicting 28-day mortality in acute-on-chronic hepatitis b liver failure [J]. Journal of Shandong University (Health Sciences), 2025, 63(6): 89-99.
[4] DU Xue, LI Chunxia, LIU Yunxia, ZHANG Tao. Dynamic prediction model for the colorectal cancer patients prognosis based on MFPC-Cox [J]. Journal of Shandong University (Health Sciences), 2025, 63(5): 101-110.
[5] YANG Weifang, XU Hong, LIU Yuantao, ZHAO Huichen. Mechanism of thyroid-stimulating immunoglobulin in Graves disease recurrence and clinical significance [J]. Journal of Shandong University (Health Sciences), 2025, 63(4): 116-121.
[6] CUI Qianqian, LI Jinpeng, WU Yudan, HOU Zhiping, SUN Weiluo, CUI Panpan, HE Peiyuan. Clinical value of fecal miRNA for non-invasive screening of advanced colorectal adenomas [J]. Journal of Shandong University (Health Sciences), 2025, 63(2): 43-50.
[7] CHANG Yu, HU Yunfeng, WANG Huifeng, GUO Jing, ZHANG Tiao, HAO Yaqin, LIU Yu. A mendelian randomization study on the association between appendectomy and the risk of colorectal cancer [J]. Journal of Shandong University (Health Sciences), 2025, 63(2): 77-83.
[8] WANG Gang, XU Pengyan, ZHAO Xuan, WANG Haifeng, GE Miaomiao, PAN Huafeng, JIANG Zhiwei. Effect of ω-3 polyunsaturated fatty acids on recovery of autonomic nervous system and intestinal function after laparoscopic colorectal cancer surgery [J]. Journal of Shandong University (Health Sciences), 2025, 63(2): 36-42.
[9] WANG Xiao, KONG Wenru, CUI Weiliang, WANG Shuqi. Alstonia mairei total alkaloids enhance the sensitivity of colorectal cancer to 5-fluorouracil chemotherapy [J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 30-37.
[10] GUO Shuhua, FAN Yang, TIAN Feng, WANG Chuanxin, DU Lutao, LI Peilong, GUO Xing, XU Shuo. Role of microfibril-associated protein 3 in regulating mesenchymal transition of glioma stem cells [J]. Journal of Shandong University (Health Sciences), 2024, 62(6): 9-16.
[11] WEI Yanruoxue, LI Ziqi, LIU Chuncheng, LIU Xiaohan, ZHAO Ran, LIU Yukun. Intratumor heterogeneity of SP1 expression in colorectal cancer and its clinical significance [J]. Journal of Shandong University (Health Sciences), 2024, 62(5): 89-94.
[12] LIU Chuncheng, LIU Xiaohan, WEI Yanruoxue, LI Ziqi, LIU Yukun, ZHAO Ran. Subcellular localization pattern of bromodomain containing 9 in colorectal cancer and its clinical significance [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 24-30.
[13] YANG Xueyan, WU Yinping, LYU Li, ZHAO Zehua, MA Hangyu, LI Fengcai, WANG Kai, FAN Yuchen. Diagnostic value of dynamic changes of monocyte-to-lymphocyte ratio in acute-on-chronic hepatitis B liver failure [J]. Journal of Shandong University (Health Sciences), 2024, 62(3): 61-69.
[14] DIAO Yujie, LIN Lin, LI Wenxuan, WANG Zhouyang, JIANG Bei, HU Yingying, LIU Guangyi. Neutrophil-to-platelet ratio predicts adverse renal outcomes in anti-neutrophil cytoplasmic antibody-associated vasculitis and its synergistic multifactor optimization model [J]. Journal of Shandong University (Health Sciences), 2024, 62(2): 60-68.
[15] YU Li, WANG Yijia, YANG Yong, LIU Xuehuan, WAN Xuehua, BAO Cuiping, MIAO Beiliang, LI Siqi, LI Jing, LIU Jun. Relationship between fusobacterium nucleatum mediated autophagy and cell refractive index based on optical surface wave [J]. Journal of Shandong University (Health Sciences), 2024, 62(10): 87-97.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
Copyright 2018 © Editorial office of Journal of Shandong University (Health Sciences)
Supported by Beijing Magtech Co.Ltd