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DEREGULATION OF LNCRNA EXPRESSION characterization of this regulatory system will reveal many
IN CANCER of detailed mechanisms. As a result, these studies will help
develop novel strategies for cancer treatment. Furthermore,
It is well-known that most of lncRNAs are transcribed lncRNAs may serve as biomarkers for diagnosis/prognosis
through RNA polymerase II, just like protein-coding genes; as supported by profiling studies of clinical specimens.
they are also spliced products via canonical genomic splice Finally, given their important role in metastasis, lncRNAs
site motifs, frequently ended with a poly A tail. Importantly, may also prove to be valuable targets for cancer therapy. In
lncRNAs are often regulated by well-established particular, ribonucleoprotein complexes through lncRNAs
transcription factors and are expressed in a tissue-specific are critical to lncRNA-mediated metastasis, drugs that
manner. For example, we have shown that wild-type p53 block or enhance such interactions may have a bright future.
[77]
can transcriptionally induce linc-RoR and loc285194, but
mutant p53 cannot. [17,24] On the other hand, c-Myc, as an Financial support and sponsorship
oncogene, can regulate a group of lncRNAs. In cancer,
[78]
c-Myc is often amplified or up-regulated, which may This work was supported by NIH grant R01 CA154989
explain why some lncRNAs are often deregulated. (YM).

CONCLUSION AND PERSPECTIVE Conflicts of interest

A tremendous progress has been made in our understanding There are no conflicts of interest.
of the genes and events involved in metastasis in recent REFERENCES
years. Moreover, emerging evidence indicates that lncRNAs
have also joined this complex regulatory network and may 1. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin
serve as very important regulators at different stages of J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D,
metastasis (e.g. EMT, invasion, migration, and colonization) Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine
often through their expression levels [Figure 2]. However, R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C,
overall, lncRNA research in this field is still at the infancy Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan
stage. Given the complex interactions of lncRNAs with A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A,
DNA, RNA, and protein, a systematic approach may be Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D,
Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P,
needed to better understand the molecular mechanism of Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S,
lncRNA-mediated metastasis. With the development of Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A,
advanced technology such as CRISPR/Cas9, it is now Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R,
feasible to perform knockout or knockin experiments and Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier
these research tools will no doubt speed up new discovery. LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla
In this system, nuclease Cas9 assisted by a sequence- AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD,
Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson
specific guild RNA (gRNA) which is functionally similar DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P,
to RNAi, cuts targeted DNA sequence. Once the double Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen
[79]
strand break is made, the cell employs one of two major A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny
DNA repair mechanisms, non-homologous end joining DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM,
(NHEJ), and homologous recombination (HR). Unlike HR, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL,
the NHEJ mechanism often leads to deletions or insertions, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A,
and thus it is an error-prone repair, a feature important for Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach
J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E,
knockout. The HR mechanism would allow for introducing Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M,
mutations or correcting a mutant sequence by knockin. Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura
Increasing evidence indicates that this technology has a G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood
potential to transform the field of cancer genetics such as the L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola
development of next-generation models of human cancer. [80] AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J,
Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki
Given the nuclear localization nature for a number of K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA,
Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR,
lncRNAs, genetic manipulations at the DNA level provides de la Bastide M, Dedhia N, Blocker H, Hornischer K, Nordsiek
a better alternative to RNAi approach which mainly works G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou
through RISC complex in the cytoplasm. Our recent study S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC,
indicates that a dual gRNA/Cas9 system combined with Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE,
donor vector for HR can greatly improve the efficiency Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler
of obtaining complete lncRNA knockouts in various D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif
S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I,
cancer cell lines. As this field advances, we anticipate Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran
[81]
that more lncRNAs will be identified to be important JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G,
players in cancer metastasis. More importantly, further Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 7