Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characteristics and Survival

Clinics of Oncology
ISSN: 2640-1037
Research Article
Deadenylase Expression in Small Cell Lung Cancer Related To
Clinical Characteristics andSurvival
Kokkori1 I2*
, Maragozidis P2
, Antonopoulos D2,3
, Kyritsis A2,3
, Balatsos NAA2
, Gourgoulianis KI3
.
1
Department of Respiratoryand Oncology, Theageneio Hospital, Thessaloniki, Greece
2
Department of Biochemistry and Biotechnology, University of Thessaly, Greece
3
Department of Respiratory Medicine, University of Thessaly, Greece
Volume 2 Issue 3- 2020
Received Date: 27 Jan 2020
Accepted Date: 15 Feb 2020
Published Date: 19 Feb2020
2. Keywords
SCLC,Deadenylases,PARN,
Survival, Biomarker 3
3. Introduction
1. Abstract
1.1. Aim: Lung cancer is the second common malignancy and the most aggressive cancer worldwide
with late diagnosis and poor prognosis. The search for biomarkers that promote early diagnosis and
improve therapeutic strategies focuses to the understanding of the mechanisms underlying cancer
development and progression. The deregulation of gene expression is one of the cancer hallmarks
reflected to the stability of mRNAs. The latter is determined by the removal of their poly (A) tails,
which is catalysed by deadenylases. Herein, we analysed the expression levels of deadenylases in Small
Cell Lung Cancer (SCLC) Clinical Samples and correlated them with the Clinical Characteristics and
the Survival of Patients.
1.2. Patients and Methods: Computational transcriptomic analysis was performed to examine the
expression of deadenylases in SCLC. Bronchoscopy lung biopsies from 19 patients were collected and
subsequently analysed with real-time Polymerase Chain Reaction (PCR) to determine the levels of
deadenylases.
1.3. Results: PARN, CNOT6, CNOT7 and NOC deadenylases were expressed in both malignant and
non-pathological lung sample tissues. They were differentially expressed in malignant tissue compared
to matched non-pathological samples. Older patients had increased expression of PARN (68.5 + 6.7
versus 59.7 + 6.2 years). Increased PARN levels correlated to decreased overall survival of 180 days.
Similar results were obtained for CNOT6 andCNOT7.
1.4. Conclusion: Deadenylases are relevant to the development of carcinogenesis in SCLC as their
altered levels affect the gene expression. PARN represents a promising prognostic biomarker and
therapeutic target in a generally unknown disease like SCLC.
recognition and biomarker search has to focus on the mechanisms
Worldwide, lung cancer is the most common cause of major cancer
incidence and mortality, primarily because it is detected in an
advanced stage for both sexes. Among lung cancers, SCLC is the
most aggressive type and accounts for 13 to 15% of all lung cancer
cases [1]. The pathogenesis of the disease is still complex and
unclear. Thus, the search ofbiomarkers for diagnosis, prognosis and
therapeutic purposes is of primary importance. In this direction,
any strategy to improve prediction, treatment outcome, early
of development and progression of the disease. As the deregulation
of gene expression is a hallmark of cancer, these mechanismsmay
be hidden behind the well-established alterations in the expression
of many oncogenes and tumor-suppressors. Such a mechanism is
the degradation of mRNA, where several factors are involved in the
process, including deadenylases and micro RNAs (mi RNAs).The
stability of mRNA, which regulates gene expression is deregulated
in malignancies, including lung cancer. Deadenylases are Mg (II)-
dependent exoribonuncleases that catalyse the shortening of
*Corresponding Author (s): Ioanna Kokkori, Department of Respiratory and Oncology, The-
ageneio Hospital, Thessaloniki, Greece, E-mail: kouirouxis@hotmail.gr
clinicsofoncology.com
Citation: Kokkori1 I, Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characteris-
tics and Survival. Clinics of Oncology. 2020; 2(3): 1-8

Volume 2 Issue 3 -2020 Research Article
Poly (A) tails of mRNAs, which is the first and rate-limiting step
of mRNA decay [2,3]. The lifetime of mRNAs depends on
changes in poly (A) tail length and consequently determines the
levels of the produced cognate. Thus, deadenylases are key
players in the expression of oncogene and tumor suppressor
genes[4-6].
PARN, the best studied mammalian deadenylase, can act as a
tumor suppressor because it is activated by the tumor–suppressor
BARD1 [7] and it plays role in the degradation of IL-8, VEGF, c-
Jun, UPA, c-FOS and TNF-alpha mRNAs, while it is involved in
the maturation of regulatory RNAs, including SNO RNAs and
telomeric RNA [8-11]. Studies about the deadenylase expression
in various types of cancer are limited. Previous work has shown
that their expression is altered in Acute Lymphoblastic Leukemias
(ALL) and Acute Myeloid Leukemias (AML) with slightly up-
regulated CNOT6 expression, down-regulated CNOT6L and
CNOT7 and up-regulated PARN [12]. CNOT6L was present in
human colon adenocarcinoma samples [13] and CNOT8 was up-
regulated in primary colorectal carcinoma and metastatic regions
compared to the normal mucosa [14]. In squamous cell
carcinoma (a subtype of non-small cell lung cancer) was a shown
differentially expressed deadenylase level in samples tissues [15].
In gastric cancer PARN expression has been studied in two cell
lines of gastric cancer origin [16]. Despite the previous works,
a study about deadenylases in SCLC is still pending. Based on
the previous data, we investigate the relationship between the
expression levels of deadenylases in both malignant and normal
lung tissue from the same patient with SCLC. Further, we correlate
this relationship with their clinical characteristics and survival. We
hypothesize that if the expression levels of deadenylases are altered
between malignant and normal lung tissues from the same patient,
it provides us with preliminary information about their role and
it may represent a useful prognostic biomarker in SCLC. It is
worth noting though that the present study aims to investigate an
4 unknown field and thus offer a novel prognostic tool in addition
to the current prognostic factors of the disease used by clinicians,
as staging, Performance Status (PS) andage.
We intend to focus on the pathogenesis of SCLC and propablyuse
a new biomarker like PARN on clinical practice hoping for new
targeted therapies in the future.
4. PatientsandMethods
4.1. Patients
Nineteen (19) patients of the study were over the age of 18 years
old from both sexes. They had positive diagnosis of SCLC from
bronchoscopy biopsy samples and they received no therapy until
the time of diagnosis (Chemotherapy, Radiotherapy or Targeted
Therapy). The individuals had no synchronous neoplasm except
in situ neck cancer or skin cancer. They did not also suffer from
other serious diseases including recent brain stroke, heart attack or
congestive heart failure. After receiving the samples, the patients
were treated with chemotherapy, radiotherapy, or both, and their
response was accorded to RECIST criteria. Bronchoscopy samples
of SCLC were collected from malignant and non-pathological
tissues (matched samples) from the same patient (n = 19), as is
summarized in (Table 1).
Samples were collected between 2010 and 2012 from University
Hospital Larissa and Theageneio Cancer Hospital, under the
approval of the Ethics Committees. The normal tissues were from
the normal lung or from another lobe of the pathological lung of
the same patient and the samples were reserved directly at -80o
C .
4.2. Methods
We performed the computational trascriptomic analysis in small
cell lungcancer usingmicroarraydata from the Oncomine database
[17, 18]. Subsequently total RNA was extracted from the clinical
sampleswiththeTRIReagentProtocol(Sigma).RNAconcentration
was determined by spectrophotometry (BioPhotometer Plus,
Eppendorf). Comparative quantification of deadenylase mRNAs
wasanalysed byquantitativeReal TimePolymeraseChainReaction
(Real-TimePCR). After RNAextraction, cDNAequivalent to20ng
oftotal RNA was subjected to qPCRusing the Stratagene Mx3005P
Real-Time PCR System (Stratagene Agilent Technologies) following
the manufacter’s protocol (KAPA SYBR Fast Universal qPCR kit,
KAPA Bio systems). PCR data and the relative expression results
wereanalyzedbyMx3005Psoftware(Stratagene)andmRNAlevels
samples were compaired to their paired ones and expressed as log2
fold-change (FC).
5. Results
5.1. Computational Transcriptomic Analysis of Deadenylase
Expression in Small Cell Lung Cancer
We used computational transcriptomics in order to study the
expression of deadenylases in SCLC in comparison with normal
tissue serving as control. Microarray data from the Oncomine
database17showedthatPARNexpressionwassignificantlyreduced
in 6 SCLC samples compared to 17 healthycontrols (p=5.00) while
the expression profiles of the deadenylases ANGEL1 (p=0.100),
ANGEL2 (0.256), PAN2 (0.164) and CNOT8 (p=0.380) did not
Differ significantly (Figure.1). The analysis [18] showed also that
CNOT7 was significantly increased in 5 SCLC samplescompared
Copyright ©2020 Kokkori1 I al This is an open access article distributed under the terms of the Creative Commons Attribution License, 2
which permits unrestricted use, distribution, and build upon your work non-commercially.

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Figure1: Transcriptomics analysis of expression of deadenylases in Small Cell
Lung Cancer (SCLC) from the Oncomine database. Differential mRNA expression
of deadenylases in SCLC. PARN is significantly decreased in Bhattacharjee Lung
study (p=5.00). CNOT7 is significantly increased in Garber Lung study (p=0.037).
The expression of ANGEL1, ANGEL2, PAN2, CNOT8, CNOT6 and CNOT6L was
not significantly altered in SCLC. In both cases the sample size very small to inter-
pret with caution.
to 6 healthycontrols (p=0.037) while CNOT6 (p=0.173), CNOT6L
(p=0.096), ANGEL1 (p=0.126), ANGEL2 (p=0.156) and PAN2
(p=0.146) were not significantly different between SCLC and
normal control samples (Figure 1).
5.2. Differential expression of deadenylases in SCLC
The differential mRNA expression of deadenylases in the
computational transcriptomic analysis increased our interest in
samples from patients with SCLC, so we examined their expression
in malignant and non-pathological samples from the same patient.
Weanalyzed the mRNA levels of deadenylases by quantitative RT-
PCR in SCLC specimens against their matched normal tissues. We
collected clinical data of patients like age, sex, smoking history
and staging of disease and correlated the expression levels of
deadenylases with clinical data above and with their survival.
TheexpressionofANGEL1, ANGEL2,PARNL,CNOT8andPAN2
deadenylases had not differences between the matched samples.
PARN and CNOT7, belonging to DEDD nucleases, and CNOT6
and NOC, belonging to EEP nucleases, altered their expression
profile significantly. As shown in (Figure 2) in 13 SCLC patients
Figure 2: Comparative quantification of deadenylase expression in SCLC. PARN
(rhombus), CNOT6 (square), CNOT7 (triangle) and NOC (circle) mRNA levels
with real -time PCR in SCLC lung biopsies and expressed as log2 fold-change. Each
point corresponds to the relative expression of the deadenylase in malignant tissue
compared to the corresponding adjacent non-malignant tissue. The expression of
the non-malignant tissue was set as 0. p<0.05.
(68.4%) PARN mRNA levels were elevated (log2
Fold Change
(FC)>0), while in 6SCLC patients (31.6%)theywere reduced (log2
FC<0). CNOT6 levels were elevated in 10 patients (55.5%) and
they were reduced in 8 (44.5%). CNOT7 levels were elevated in 12
(66.65%) patients and in 6 (33.4%) were reduced. NOC was over
expressed in 7 (53.8%) patients andunder expressed in 6 (46.2%). 6
5.3. Deadenylase Expression Levels and Clinical
Characteristics
The correlation between the deadenylase expression with the
clinical characteristics and the survival of patients were further
analyzed after having divided the patients in two groups according
to the expression levels of deadenylase (increased or decreased)
likein previous work in SCC15. Weinvestigatedcharacteristics like
smoking history and age.
We found no correlation with the smoking history of the patients.
Older patients had increased PARN levels than younger ones
+(68.56.7 vs. 59.7+6.2 years, p=0.014) as shown in (Figure 3).
5.4. Deadenylase expression levels andsurvival
The relationship between PARN, CNOT6 and CNOT7 expression
with survival is described by means of Kaplan-Meier curves.
Patients with increased PARN levels had lower survival of 180
days (234 vs. 414 days, p=0.016). Similar results were obtained for
CNOT6 (224 vs. 377days, p=0.035)andCNOT7(231vs. 419days,
p=0.021) as shown in (Figure4).
Figure 3: Association of age and expression levels of PARNin SCLC samples. Old
patients overexpress PARN (68.5 6.7 vs 59.7 6.2 years), p=0.014.

Figure 4: Kaplan-Meier survival curves show the correlation between expression
levelsofPARNandsurvival.Samplesweredividedintwogroups,wheredeadenylase
expression levels are either increased or reduced, between the malignant sample and
the matched non- pathological one.
The red line shows the overall survival in patients overexpressing PARN which is
lower by 6 months than in patients who underexpress PARN (blue line), p=0.016.
Figure 4: Association of expression levels of CNOT6 and survival. The red line
shows the overall survival in patients overexpressing CNOT6 which is lower by 153
days than in patients who underexpress CNOT6 (blue line), p=0.035.
Figure 4: Association of expression levels of CNOT7 and survival. For patients
who overexpress the enzyme (red line), overall survival is 188 days lower compared
to patients that underexpress it (blue line),p=0.021.
The graphs above indicate the different correlation between the
expression levels of deadenylases PARN, CNOT6 and CNOT7
and patient’s survival. As we can see, high expression of PARN is
correlated with lowest survival curve, which could play the role of
a corestone biomarker in patients with SCLC. In addition to the
expression levels of CNOT6 and CNOT7 were detected as highto
the patients with lower survival. This result could indicate thatthe
high expression of deadenylases may interfere as a possible cancer
biomarker in future clinical diagnostics inSCLC.
6. Discussion
As the study on the detection of deadenylase levels in SCLC is
still pending, the gene expression profile has to be compared with
studies on other types of cancer. Our search in computational
transcriptomic analysis showed that PARN expression was
Significantly reduced18 while CNOT7 expression was
significantly increased [18] but in both cases the sample size is
very small, so interpret should be with caution. The results in our
study suggest that PARN, CNOT6, CNOT7 and NOC levels are
altered in SCLC compared to healthy samples. The expression of
ANGEL1, ANGEL2, PARNL, CNOT8 and PAN2 was not
significantly altered. PARN over expression was observed in
68.4% of patients, while 7 older patients had increased PARN
levels than the younger ones (68.5+6.7 vs. 59.7+6.2 years). PARN
over expression was observed in patients with decreased overall
survival by 180 days (234 versus 414 days for PARN over
expressed vs. under expressed, respectively; p=0.016). Similar
results were obtained for CNOT6 and CNOT7.
Work from our team showed that the expression of several
deadenylases is altered in SCC [15]. PARN, CNOT6, CNOT7
and NOC were differentially expressed in SCC clinical samples
compared to healthy controls, while PAN2 and CNOT8 were
barely detectable. PARN over expression was correlated with
younger patients and CNOT6 over expression with non-metastatic
tumors. The increased levels of PARN and NOC were observed in
patients with increased overall survival. These two types of lung
cancer are characterized by differences in molecular and clinical
level although both appear to heavy smokers [19, 20].
The results described in this work on SCLC suggest that the
expression of ANGEL1, ANGEL2, PARNL, CNOT8 and PAN2
deadenylases showed no differences between the malignant and
normal tissue samples. PARN, CNOT6, CNOT7 and NOCmRNA
expression didn’t vary between normal and cancer lung tissues.
Furthermore, no correlation between smoking history of patients
and lung cancer was found, but it was observed that older patients
had increased PARN levels compared to younger patients. Finally,
it was observed how the expression levels of deadenylases PARN,
CNOT6 and CNOT7 affected patient’s survival curves. It came as
a conclusion that high expression levels of PARN, CNOT6 and
CNOT7, may lead to lower patients’ survival, naming them as
possible cancer biomarker and a clinical tool of possible low
viability.
It is interesting that PARN, CNOT6, CNOT7 and NOCexpression
levels are altered in SCCandSCLC malignant samples compared to
healthy controls and especially with over expression of PARN and
NOC (Table 2). PARN over expression is associated with longer
survival in SCC but with decreased in SCLC as seen in (Table 3).
Our knowledge on the role of deadenylases in SCLC is limited.
There is growing interest to elucidate the underlying protein
profiles in SCLC. The study of proteomics in SCLC showed that

Table 1. Patient characteristics
Individuals,n 19
Age (median) 65.73
Sex (male/female) 18 / 1
Pys (median) 68
Smokers/ex smokers 17 / 2
Staging (extensive/limited) 16 / 3
Survival (median) 9.8 months
Table 2. Comparison of the expression levels of deadenylases between
SCLC and SCC.
P A R N
Hi g h a
(%)
CN O T6
H i g h a
(%)
CN O T7
H i g h a
(%)
N O C
Hi g h a
(%)
SCLC 68.4 55.5 66.6 53.8
SCC 52 48 48 56
Table 3. Comparison of the association between PARN and NOC
expression levels with clinical outcome in SCLC and SCC
PARNa NOCa
SCLC 6 MONTHSb 0 MONTHSc
SCC 7 MONTHSd 7.9 MONTHSd
KHSRP, which belongs to RNA-binding proteins, is involved in
degradation of inherently unstable mRNAs that contain AU-rich
elements (AREs) in their 3-UTR, possibly by recruiting
degradation machinery to ARE-containing mRNAs by recruiting
PARN [21]. This protein is overproduced bychemo resistant SCLC
cells GCLC1-M13 compared to GCLC1 cells. The first cell line is a
sub-clone of GLC1 obtained through selection of cells cultivated in
serum starved medium and limited dilution [22].
KHSRP is overproduced in SCLC compared to NSCLC, which
has been studied in 3 SCLC cell lines (NCI-H69, NCI-H82 and
NCI-H209) and 3 NSCLC cell lines (A549, NCI-H23 and NCI-
H520) [23]. The role of KHSRP in SCLC is further investigated in
the Oncoming database microarray. It is significantly over
expressed in SCLC compared to normal lung tissue and other lung
cancers in lung microarray data[18].
No significant interactions with any deadenylases were found in
two studies of proteomics [24, 25]. The proteomic data in SCLC
did not show increase of deadenylase production but increased
production of RNA binding proteins, especially of KHSRP which
directly interacts with PARN.
TheroleofPARNin cancer iscurrentlyunder investigation.InSCC,
PARN expression was increased in 88.8% of patients <65 years old.
PARN was silenced in cells of squamous origin and the microarray
analysisidentified233upregulatedmRNAs, probablydirect targets
of PARN. Lee and coworkers studied PARN in mouse my oblasts
and reported genome-wide analyses following PARNknockdown.
In particular, following PARN silencing factors responsible for cell
migration and adhesion were stabilized [26,27].
Recently, a feedback mechanism seemed to exist between
phospholipase D (PLD2) and PARN which is deregulated in breast
cancer cells and facilitates over expression of PLD2, protein highly
relevant to cell migration and metastasis [28]. Taken togetherwith
previous observations in SCLC, SCC, acute leukemias, gastric
cancer and breast cancer show that PARN could be used as a
potential cancer biomarker.
Nocturnin (NOC) is the only deadenylase driven by the circadian
clock and the metabolism of lipids and sugar [29]. The study of
SCC revealed that NOC was also over expressed in 56% of patients
and correlated with prolonged survival. In our study NOC was
also over expressed in 7 patients (53.8%) but no correlation with
survival was observed.
In this study we compared the deadenylase expression levels in
samples of lung tissue from the same patient. Taken into
consideration of previous observations on the role of deadenylases
in cancer, our results show that deadenylases, and especially PARN
may play an important role in SCLC carcinogenesis. PARN over
expression wasassociatedwith worsesurvival (180days)anditmay
be a prognostic marker of the disease. This might be ofsignificant
clinical importance in SCLC as PARN could be useful as a new
biomarker in this aggressive disease and contribute to the better
management of the disease. The idea and the need of new targeted
therapies may be partially answered by PARN in daily clinical use.
7. Conclusion
We have shown that the expression of deadenylases is altered in
SCLC. PARN,the best studieddeadenylase, isassociated witholder
patients and worse survival. PARN may be a promising prognostic
marker for a particularly aggressive cancer, like SCLC.
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