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the successful delivery of the double-stranded small RNA molecules
to the target cells. There are mainly two types of short RNAs: (1)
small interfering RNA (siRNA) and (2) microRNAs (miRs) involved
in RNAi-mediated genes silencing [ 1 ]. Another type of small non-
coding RNA molecules, known as piwi-interacting RNA (piRNA),
also induces genes silencing in cells [ 7 , 8 ]. RNAi can be introduced
into cells by direct delivery of synthetic small RNA (siRNA), or by
plasmid/viral vector system that express short hairpin RNAs (shR-
NAs). The later groups are subsequently processed to siRNA by the
cellular machinery and inhibit their target genes expression [ 4 ].
Briefly, inside the cytoplasm, the double-stranded siRNA separated
into two single-stranded RNA—the passenger strand and the guide
strand by a multi-protein complex called RNA-induced silencing
complex (RISC). Subsequently, the passenger strand degraded and
the guide strand (antisense strand) incorporated into the RISC. This
guide strand RNA-RISC complex locates and pairs with the com-
plementary sequence of mRNA and induces cleavages by Argonaute
2 (Ago 2), the catalytic component of RISC complex, resulting in
mRNA degradation and thereby preventing its translation and pro-
tein expression [ 2 , 9 , 10 ].
Recent studies demonstrated that RNAi-mediated silencing of
key genes have shown promising results to develop potential thera-
peutic targets against esophageal adenocarcinoma [ 11 – 20 ].
Suppression of adenocarcinoma-associated antigen AGR2 with
shRNA in esophageal adenocarcinoma cells had shown remarkable
growth reduction both in vitro and in vivo [ 20 ]. Also, knockdown
of insulin-like growth factor binding protein 2 (IGFBP2) by RNAi
sensitized esophageal adenocarcinoma cells to the cisplatin treat-
ment [ 12 ]. These results suggest that targeted inhibition of IGFBP2
may be an effective approach for sensitizing esophageal adenocarci-
noma to standard chemotherapeutic agents. Silencing of micro-
somal prostaglandin synthase-1 (mPGES-1) with RNAi showed
reduced production of prostaglandins (hormone-like substances-
play important role in the progression of different cancers including
esophageal adenocarcinoma). This in turn, inhibited proliferation
and enhanced apoptosis of esophageal adenocarcinoma [ 13 ].
Downregulation of Akt1 and Gli-1 by shRNA led to the inactiva-
tion of ligand Indian hedgehog pathway, which significantly inhib-
ited the viability of esophageal adenocarcinoma cells [ 16 ]. In
addition, chemotherapy targeting ErbB2-PI3K-mTORC1 signal-
ing axis by trastuzumab (Her 2 receptor blocker that inhibits P13K/
Akt pathway) and BEZ235 (dual inhibitor of P13K and mTOR) as
well as, combining with RNAi targeting Akt1 and Gli-1, resulted in
higher reduction of cancer cell growth [ 16 ]. These findings imply
that suppression of crucial genes with RNAi in combination with
conventional therapy may provide a new therapeutic strategy for
effective management of patients with esophageal adenocarcinoma.
Table 1 summarize the RNAi approaches used in esophageal adeno-
carcinoma to find out potential therapeutic modalities.Farhadul Islam et al.