Documente Academic
Documente Profesional
Documente Cultură
Vy Nguyen
Keywords
lncRNA, cancer therapy, misregulation, tumorigenesis, tumor suppressing proteins
Abstract
The most common cancer therapies, chemotherapy, radiation, and surgery, are generalized and often ineffective. As a result, scientists have been searching for more targeted drugs to treat tumors. New studies have focused on long non-coding RNA (lncRNA), non-coding RNA molecules greater than 200 nucleotides in length. lncRNA has long been associated with essential cell functions, such as control of gene splicing, translation, and transcription. lncRNA has also been linked to cancer, with evidence showing that cancer cells often exhibit abnormally high or low levels of lncRNA. Recent studies from 2012 have focused on defining the specific molecular pathways connecting lncRNA and tumorigenesis. By discovering the tumor-suppressing proteins linked to misregulated lncRNA, researchers have been able to propose possible cancer treatments involving the artificial regulation of lncRNA. This literature review outlines recent findings in lncRNA and cancer and identifies potential applications for the future.
Introduction
Chemotherapy, the most widely used treatment against cancer, is designed to kill rapidly dividing cells in the body. While cancer cells fit under this category, beneficial cells such as skin, hair, stomach, and blood cells do as well. As a result, cancer patients undergoing chemotherapy experience side effects such as loss of hair, cognitive impairment, and nausea.1 In addition, chemotherapy is often ineffective and only able to put cancer temporarily at bay. Because chemotherapy is such a generalized treatment, scientists have been searching for a more specialized drug to treat cancer. Cancer, they have discovered, is caused by the misregulation of growth factors in a cell.2 For example, cancer cells do not properly respond to signals limiting cell growth and promoting cell death and differentiation. However, the cause of this misregulation has been linked to a whole diversity of factors, including chemical exposure, abnormal proteins, and viruses.3 In order to dive closer to the root of the cause, recent studies have focused on non-coding RNA (ncRNA.) Non-coding RNA, though they do not translate into proteins, are key in regulating gene expression in the cell.4 Abnormalities in ncRNA activity could mean irregular growth in cells that lead to ongogenesis. Scientists have found evidence linking a certain type of noncoding RNA, known as long non-coding RNA, to various types of cancer.
molecules is long non-coding RNA (lncRNA). lncRNA, broadly defined as non-coding RNA molecules that are 200 nucleotides or greater in length,5 can be present in the thousands within a single cell. While lncRNA was at first believed to be transcriptional junk,6 new research has shed light on the important role lncRNA plays in cells.
lncRNA in cancer
lncRNA appears to play a part in carcinogenesis, making it the subject of several recent studies. Cancer cells frequently exhibit abnormally high or low levels of lncRNA. Recently, researchers have uncovered several pathways between which lncRNA and cancer are linked. This section outlines some of these ways that lncRNA contributes to tumor formation and growth.
Upregulation
The term upregulation refers to the increased transcription of a specific RNA molecule in a cell so that it is present in larger quantities. In some cases, upregulation of certain lncRNA transcripts leads to the greater proliferation of cancer cells. For instance, the lncRNA highly-upregulated in liver cancer (HULC) is, as the name suggests, present in abnormally high amounts in heptatocellular carcinoma (HCC).9 Gastric cancer cells have exhibited high levels of H19, another lncRNA transcript.10 In these cases, the lncRNA appears to interfere with the creation of tumor suppressor proteins. For example, HBx, a hepatitis B viral protein, causes the upregulation of HULC by interfering with the CREB transcription factor. The altered CREB factor causes increased transcription of HULC. HULC, in turn, downregulates p18, a tumor suppressor gene. Because the gene was silenced, less p18 proteins were being produced, and thus the HCC cells were was allowed to grow and migrate. H19, on the other hand, is linked to gene p53. p53 prevents tumor formation by promoting cell death and preventing cell proliferation. H19 partially inactivates the p53 gene, which in turn causes lower amounts of p53 target protein Bax to be produced in the cell. Without Bax, the cell can replicate without restraint, causing the gastric tumor. In fact, one of the first lncRNA transcripts discovered, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), has been linked to multiple types of cancer (see table 1, row 3).11 MALAT1 is actually highly expressed in healthy cells. It is an important regulating factor in cell migration, formation, and apoptosis.3 However, cancer tumors have shown excessive levels of MALAT1 expression. It is not the mere presence of these lncRNA molecules that causes tumors to grow. Rather, it is the misregulation of the transcripts that is the cause.
P-value P < 0.0001 P < 0.05 P = 0.012 P < 0.05 P < 0.05
TABLE 1: A comparison of cancer-linked lncRNA transcripts This table compares differences and similarities between several lncRNA transcripts by cancer type, misregulation, associated tumor suppressing protein, and p-value. Note that MALAT1 is capable of affecting several types of cancer, and that p53 is linked to multiple regulatory lncRNAs.
Downregulation
The upregulation of lncRNA is not always associated with cancer tumorigenesis. Downregulation of lncRNA can also cause tumor growth. In brain tumor cells, the expression of lncRNA maternally expressed gene 3 (MEG3) is actually decreased.12 MEG3 regulates cell proliferation by association with tumor suppressor gene p53. When MEG3 is not expressed, p53 is also not expressed, allowing the glioma cells to grow uncontrollably. The lncRNA molecule actually has a tumor suppressing effect. The connection between lncRNA and the tumor suppressing protein can be indirect. The novel lncRNA LOC554202 is the host gene to micro RNA miR-31, a tumor suppressing gene involved in triple-negative breast cancer (TNCB).13 TNCB cells show abnormally low levels of both LOC554202 and miR-31, suggesting their connection. miR-31 then suppresses several metastasis-promoting genes, including RhoA and WAVE3, which are linked to p53. LOC554202, in this case, is only a part of a long chain of gene interactions, which could be detrimental when developing TNCB treatments based on LOC554202. For instance, LOC554202 and miR-31 appear to be regulated epigenetically via CpG island hypermethylation. When researchers altered the DNA methylation in an attempt to upregulate LOC554202 and miR-31, the miR-31 levels did not reach those of the lncRNA host transcript. This could possibly be attributed to other factors regulating mi-R31, making LOC554202 an ineffective target for therapy.
therapy, being able to identify the type of glioma could help oncologists tailor a more effective, personalized treatment for their patient. However, at this time, the lncRNA expression patterns for other types of tumors are poorly characterized. Future work in this area could bring lncRNA analysis closer to practical clinical application.
Conclusion
lncRNA has long been associated with cancer genesis. However, the molecular pathways between cancer cells and lncRNA are only beginning to be understood. Research suggests that misregulation of lncRNA whether through down or upregulationcould be the root of the cause of cancer. Each new discovery brings another potential route for targeted cancer therapy by manipulation of lncRNA expression. In addition, unique lncRNA expression patterns between cancer cells could help differentiate between various types of tumors. lncRNA-based treatment could be a future path for clinical oncology.
Acknowledgements
I would like to thank my peer reviewers, Caitlin Morelli and Dylan Kaufman, for their invaluable comments and critiques. I would also like to thank Dr. Cecelia Musselman for her input on the grammar and missing points of this review. Finally, I would like to thank Shailja Modi for proofreading this review for spelling and grammatical errors. Without these people, this paper would not have been possible.
Works Cited
1. Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, and Wilson C. 2012. Objective and subjective cognitive
impairment following chemotherapy for cancer: A systemic review. Cancer Treatment Reviews. 38(7): 926934. DOI: 10.1016/j.ctrv.2012.05.002. 2. Kaida D, Scheider-Poetsch T, Yoshida M. 2012. Splicing in oncogenesis and tumor suppression. Cancer Science. 103(9): 1611-1616. DOI: 10.1111/j.1349-7006.2012.02356.x.
3. Xi LF, Schiffman M, Koutsky LA, Hulbert A, Lee SK, DeFilippis, V, Shen ZP, and Kiviat NB. 2012. Association of
human papillomavirus type 31 variants with risk of cervical intraepithelial neoplasia grades 2-3. International Journal of Cancer. 131(10): 2300-2307. DOI: 10.1002/ijc.27520.
4. Maenner S, Muller M, and Becker PB. 2012. Roles of long, non-coding RNA in chromosome-wide transcription
regulation: Lessons from two dosage compensation systems. Biochimie. 94(7): 1490-1498. DOI: 10.1016/j.biochi.2011.12.026.
5. Prensner JR and Chinnaiyan AM. 2011. The Emergence of lncRNAs in Cancer Biology. Cancer Discovery. 1(5): 391407. DOI: 10.1158/2159-8290.CD-11-0209.
6. Pandey R and Mukerji M. 2011. From JUNK to Just Unexplored Noncoding Knowledge: the case of transcribed Alus.
Briefings in Functional Genomics. 10(5): 294-311. DOI: 10.1093/bfgp/elr029.
7. Caley DP, Pink RC, Trujillano D, and Carter DRF. 2010. Long Noncoding RNAs, Chromatin, and Development. The
Scientific World Journal. 10: 90-102. DOI: 10.1100/tsw.2010.7.
8. Johnson R. 2012. Long non-coding RNAs in Huntingtons disease neurodegeneration. Neurobiology of disase. 46(2):
245-254. DOI: 10.1016/j.nbd.2011.12.006.
9. Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, Zhang X. 2012. Elevation of Highly Up-regulated in Liver
Cancer (HULC) by Hepatitis B Virus X Protein Promotes Hepatoma Cell Proliferation via Down-regulating p18. Journal of Chemical Biochemistry. 287: 26302-26311. DOI: 10.1074/jbc.M112.342113.
10. Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J, Fang G. 2012 Sep. Up-regulated long non-coding RNA H19 contributes to
proliferation of gastric cancer cells. Federation of European Biochemical Societies Journal. 279(17): 3159 3165. DOI: 10.1111/j.1742-4658.2012.08694.x.
11. Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, Wu LM, Chen LM, Zheng SS. 2012 Sep. Long non-coding RNA
MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Medical Oncology. 29(3): 1810-1816. DOI: 10.1007/s12032-011-0004-z.
12. Wang P, Ren Z, Sun P. 2012. Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell
proliferation. Journal of Chemical Biochemistry. 113(6): 1868-1874. DOI: 10.1002/jcb.24055.
13. Augoff K, McCue B, Plow EF, and Sossey-Alaoui K. 2012. miR-31 and its host gene lncRNA LOC554202 are regulated
by promoter hypermethylation in triple-negative breast cancer. Molecular Cancer. 11(5). DOI: 10.1186/14764598-11-5.
14. Zhang X, Sun S, Pu J, Tsang A, Lee D, Man V, Lui WM, Wong S, and Leung G. 2012. Long non-coding RNA
expression profiles predict clinical phenotypes in glioma. Neurobiology of Disease. 48(1): 1-8. DOI: 10.1016/j.nbd.2012.06.004