A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo
Authors: Jing Qin
Gui-Lan Wang
Yuan-Yuan Zhu
Yu-Yin Xu
Li Chen
Jia-Ming Zhou
Yi-Xin Zhang
Yin-Ze Wei
Journal: BMC Cancer (2013)
Discipline: CLINICAL MEDICINE
Keywords: synthetic dsRNA; TLR3; interferon pathway; angiogenesis; tumor cells
Affiliations: Department of Pathological Anatomy, Nantong University, Nantong, China. .

Abstract:  Background: Recent studies have demonstrated that synthetic dsRNAs may produce therapeutic effects in a target-independent manner through stimulation of the toll-like receptor-3 (TLR3)/interferon pathway; as a result, angiogenesis and proliferation of tumor cells are inhibited. Thus, this pathway may become a potential target of dsRNA in tumor suppression. In this study, we evaluated the role of synthetic dsRNA as a TLR3 synergist and by combining with sorafenib in anti-hepatocellular carcinoma (HCC) in vitro and in vivo. Methods: Four dsRNAs were designed and synthesized. One of them that was capable of activating TLR3 most effectively in human HCC cell line (HepG2.2.15) was selected as a TLR3 synergist (called BM-06). Subsequently, the expression of proteins relating to TLR3 signaling pathway, such as NF-Œ∫B, caspase 8 survivin, bcl-2 and PCNA affected by BM-06, sorafenib alone or in combination, was compared. The migration, proliferation and apoptosis of HepG2.2.15 cells were evaluated in presence of BM-06, sorafenib alone or in combination of both. The similar treatments were also applied in an SD rat primary HCC model. Results: qRT-PCR data showed that the expression of TLR3 and NF-Œ∫B in HepG2.2.15 cells was enhanced. BM-06 was selected as a TLR3 synergist capable of activating the TLR3/interferon pathway most effective among 4 synthetic dsRNAs. The migration and proliferation were significantly inhibited in treated HepG2.2.15 cells with BM-06 or Sorafenib alone as compared with PBS-sham control (P&lt;0.01). However, the role of combination BM-06 with Sorafenib was the most prominent. Tumor cell apoptotic rate was increased by BM-06 or combination when compared to PBS or poly(I:C) (P&lt;0.05). Similarly, in orthotopic HCC SD rats, the effect of the combination was superior to either agent alone on the inhibition of tumor growth and induction of HCC cell apoptosis (P&lt;0.05). Conclusions: dsRNA alone was capable of inhibiting the proliferation of HepG2.2.15 cells and tumor growth of orthotopic HCC SD rats, but the effect of combination of dsRNA with sorafenib was more prominent. These findings implicate the potential role of combined use of a dsRNA, a TLR3 synergist, and sorafenib in inhibition of HCC. 

Retracted: No

PubPeer comments:
 I am a bit concerned about similarity in other articles on the same subject. Fig 2b is very similar to Fig1c in Chen et al (10.3892 or.2012.1791). However, they depict the same conditions. Fib 3b, condition srfn is very similar to Fig6, condition dsRNA from Chen et al (10.1155 2015 572171) and to Fig4a, condition BM-06 in Chen et al (10.3892 or.2012.1791). In the same image, the control is similar to the one in Chen et al (10.3892 or.2012.1791). Finally, the poly(I:C) condition is similar to the one in Chen et al (10.3892 or.2012.1791) and come with different values (19.94 in this article vs a value above 20% in the second article). Fig 3c is very similar to Fig4b in (10.3892 or.2012.1791). The picture in condition sorafenib also appears to be very similar to condition poly(I:c) in the same figure. , 
 ## Heochst staining Images for conditions srfn and poly(I:C) from Fig 3c appear similar  and are similar to Fig4b from Chen et al [1]  ## FACS results Condition srfn appear similar to condition BAM-06 from Chen et al [1]   ## Western blot results Western blot results also appear similar in both publications   [1] https: pubmed.ncbi.nlm.nih.gov 22552584 ,