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Page 2 of 10 Farghaly et al. Hepatoma Res 2018;4:41 I http://dx.doi.org/10.20517/2394-5079.2018.30

INTRODUCTION
Hepatitis C virus (HCV) infection is the most common cause of chronic liver disease that is considered as
the common sign of liver transplantation in United States, Australia and European countries. Almost 3% of
global population are infected with HCV which mean approximately 180 million people worldwide. HCV
[1,2]
belongs to the family Flaviviridae which replicates in the cytoplasm of liver hepatocytes . HCV acute
infection is most often asymptomatic leading to chronic infection of about 75% patients. The manifestation
of chronic HCV is directly alternated from asymptomatic state to cirrhosis and hepatocellular carcinoma
(HCC) phase. Indeed, HCV infection is slowly progressed without clinical appearance in the liver of many
patients. Therefore, approximately 20%-30% of infected individuals may develop liver cirrhosis over 20 to 30
years period of infection . HCV genome encodes a large open reading frame (ORF) which have translated
[3]
into polypeptide chain with approximately 3000 amino acids that have cleaved into ten proteins. Three
structural proteins including the core, E1 and E2, in addition to five non structural proteins contain NS3
[4]
(helicase/protease), NS4A, NS4B, NS5A, and NS5B (RNA-dependent RNA polymerase) . HCV entry to
the host involves a complex series of interactions including attachment, fusion and entry. Attachment of
HCV with host receptor and co-receptors is facilitated by heparin sulfate proteoglycans that are expressed
on hepatocytes surface. Meanwhile, LDL receptor (LDLR) binds to HCV and promotes its virion entry in
pH-dependent by clathrin-mediated endocytosis . During entry process, many cellular factors have been
[5-7]
identified, including the scavenger receptor class B type I (SRB1), CD81, tight junction proteins, claudin-1
(CLDN1) and occludin (OCLN) . SRB1 and CD81 have been identified as binding partners of HCV that are
[8,9]
highly expressed in the liver and increase the selective uptake of HDL cholesterol esters into hepatocytes [9,10] .
Interestingly, targeting of these receptors and others cellular factors provides potential avenues to prevent
HCV infection and suggests that modulation of their physiological role does not lead to significant toxicity
on host cells. Generally, treatment of HCV contains several drugs that directly interact with viral proteins
such as symeprevir, grazoprevir and asunaprevir (NS3 inhibitors) which inhibit HCV-NS3 proteases [11,12] .
Several drugs target HCV-NS5B polymerases (NS5B inhibitors) such as sofosbuvir and dasabuvir, while
others interact as NS5A inhibitors such as daclatasivir, elbasvir and ledipasvir .
[13]
Importantly, over-use of antiviral drugs is considered as a factor for development of viral-escape mutation,
which leads to rapid HCV resistance. Recently, genome wide RNAi screening revealed many host cell factors
that are essential for the replication of HCV . These factors are attractive candidates for potential antiviral
[14]
medications as it is less likely that HCV will develop resistance rapidly to drugs that target host cell factors.
Several studies have been reported on the essential role of heat shock treatment and its associated proteins
(HSP) during viral replication including HSP27, HSP70 and HSPB8 [15-17] . Such stress proteins have crucial
impact in viral entry, activation, life cycle and assembly of human immunodeficiency virus (HIV) . HSPB8
[15]
showed competitive antiviral activity through direct interaction with HCV-NS4B protein . Further, HSPs
[17]
is able to prevent the inflammatory damage and promote the production of anti-inflammatory cytokines
indicating the potential imunuoregulatory role of HSPs . Interestingly, one of HS response properties is the
[18]
activation of non-coding RNA-Alu repeats which interact as inhibitory elements of transcription process .
[19]
A variety of long non-coding RNAs molecules (lnc-RNAs) are transcribed in mammalian cells to post-
transcriptionally regulate gene expression. Lnc-RNAs play crucial roles in modulating mRNA stability,
regulating mRNA translation and mediating protein modifications. Alu non-coding element is the most
abundant repetitive RNA elements in the human genome. Recently, several studies demonstrated that Alu
molecules modulate gene expression at the post-transcriptional level [20,21] . On the other hand, ribosomal
proteins (RPs) highly contain RNA-binding sites with auxiliary functions, particularly by the viruses, which
[22]
are so adept at usurping the cellular machinery . Ribonucleoproteins are responsible for synthesis of new
proteins beside other critical functions including the fundamental three-dimensional structures of small
and large RNA molecules in ribosomal subunits . One of these ribosomal proteins is RPL22 which has the
[23]
ability to interact and support HCV-RNA translation . In the current work, we investigated the potential
[24]
up-regulation of the long RNA molecule, Alu, in response to HS in HepG2 cells that were pre-infected with