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ability to self-renew. The CSCs also contribute to gaining resistance to chemotherapy
and radiotherapy. If a cancer treatment fails to eliminate all self-renewing cancer
stem cells, residual surviving cancer stem cells are able to repopulate the tumor,
causing relapse. However, the molecular mechanisms underlying self-renewal, mul-
tipotent differentiation, and tumorigenicity remain obscure. Interestingly, let-7
miRNA levels are markedly reduced in breast cancer tumor-initiating cells but
increase with differentiation [ 10 ]. Infection of breast cancer tumor-initiating cells
with let-7-lentivirus reduced cell proliferation, mammosphere formation, the pro-
portion of undifferentiated cells in vitro, as well as tumor formation and metastasis
in NOD/SCID mice [ 10 ]. In addition, blocking let-7 using antisense oligonucle-
otides (Antagomirs) resulted in enhanced in vitro self-renewal capacity of nontumor
initiating cells [ 10 ]. Of note, overexpression of let-7 reduced the expression of the
known let-7 targets RAS and HMGA2. Therefore, let-7 seems to regulate the stem
cell-like properties of multiple breast cancer tumor-initiating cells by silencing
more than one target [ 10 ]. Interestingly, RNA-binding proteins, LIN28 and LIN28B,
which are important factors for maintaining pluripotency in stem cells, bind to the
terminal loops of let-7 family precursor miRNAs and block their processing into
mature miRNAs [ 11 ]. The contribution of LIN28 was reported, not only in pluripo-
tency but also in oncogenesis. LIN28 and LIN28B are overexpressed in primary
human tumors and human cancer cell lines. Although downregulation of the let-7
gene by LIN28 can lead to carcinogenesis, their interaction is essential for
development.
miR-15a and miR-16-1 are deleted or downregulated in the majority of chronic
lymphocytic leukemia (CLL) [ 12 ] [ 13 ], which is the most common human leuke-
mia. It is characterized predominantly by nondividing malignant B cells overex-
pressing the anti-apoptotic B cell lymphoma 2 (BCL2) protein. These miRNAs
negatively regulate BCL2 at the posttranscriptional level [ 14 ] . Furthermore, in can-
cer cells of advanced prostate tumors, the miR-15a and miR-16 levels are signi fi cantly
decreased, whereas the expressions of BCL2, CCND1, and WNT3A are inversely
upregulated [ 15 ]. Delivery of miR-15a- and miR-16-specific antagomirs into nor-
mal mouse prostate results in marked hyperplasia. Likewise, knockdown of miR-
15a and miR-16 promotes survival, proliferation, and invasiveness of untransformed
prostate cells, which become tumorigenic in immunodeficient NOD-SCID mice.
14.1.2
Oncogenic miRNAs Promote Cancer Progression
One of the most widely investigated oncogenic miRNAs is miR-21. The miR-21 has
been identified as the only miRNA commonly overexpressed in solid tumors of the
lung, breast, stomach, prostate, colon, brain, head and neck, esophagus, and pan-
creas [ 16 ]. A known target mRNA for miR-21 is programmed cell death 4 (PDCD4)
[ 17- 19 ]. PDCD4 protein levels are reduced by miR-21 in cancer cells, such as breast
and colorectal cancer cells. Furthermore, overexpression of miR-21 in a human breast
cancer cell line promoted soft agar colony formation by the downregulation of Pdcd4
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