**4. Modulated expression of some neurologic genes in PDAC with special reference to autophagy**

Our lab has identified a group of genes, which are modulated during pancreatic cancer liver metastasis [52]. The microarray data are derived from ASML rat PDAC cells that were reisolated from rat liver after they had been implanted intraportally and colonized the rat liver for various periods of time. These genes were arranged according to their fold change versus control cells (more than threefold modulation of expression) at early, intermediate, advanced, and final stages of metastasis, and the resulting genes were investigated by the Ingenuity Pathway Analysis program [53]. Among these genes, a subgroup was identified to have a dual role in

**47**

**Table 1.**

*Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer…*

neurobiology and cancer metastasis. Thus, from ca. 30,000 genes, as found in a microarray experiment, 14 genes were selected as most promising. They are shown in **Table 1**. Data describing these genes are retrieved from the NCBI database [54]. From this list, some genes attracted our attention, including the autophagy

What attracted our interest in this group of genes was that they share certain roles in cancer and neurology, and some were reported to have some direct or

The overexpression of the well-known mitochondrial enzyme MAOA, linked with many psychiatric illnesses, was shown to be associated with prostate cancer. MAOA caused neuroendocrine differentiation of prostate cancer cells through

**Gene symbol Summary**

Activating transcription factor 3 Atf3 Expression is rapidly upregulated in response to

Aristaless-like homeobox 3 Alx3 Preferential methylation of this gene's promoter is

Chloride intracellular channel 6 Clic6 Elevated expression is correlated with poor

Caveolin 1, caveolae protein Cav1 The protein helps in coupling integrins to the

Neuritin 1 Nrn1 The encoded protein promotes neurite outgrowth

Monoamine oxidase A/B MaoA/MaoB They have an important role in the metabolism of

Ly6/neurotoxin 1 Lynx1 It has the capacity to enhance nicotinic

Ramp1 Expression is increased in the striatum after

Sorcs2 These genes are strongly expressed in the central

Mark4 Expression is a potential marker for cancer, and the

prognosis in human gliomas.

Htr6 This receptor is thought to regulate cholinergic neuronal transmission in the brain.

Cacnb4 Certain mutations in this gene have been associated

Parkinson's disease.

nerve injury.

nervous system.

progression.

acetylcholine.

found.

Optineurin Optn Optineurin plays a role in normal-tension glaucoma

repeated L-DOPA administration in a rat model of

associated with advanced-stage neuroblastoma.

protein may also play a role in Alzheimer's disease.

Ras-ERK pathway and in promoting cell cycle

suggesting its role in promoting neuritogenesis.

neuroactive and vasoactive amines in the central nervous system and peripheral tissues.

acetylcholine receptor function in the presence of

with idiopathic generalized epilepsy (IGE) and juvenile myoclonic epilepsy (JME). Multiple transcript variants for different isoforms have been

and adult-onset primary open angle glaucoma.

*DOI: http://dx.doi.org/10.5772/intechopen.80981*

indirect link to autophagy.

**Upregulated genes**

Receptor (G protein–coupled) activity modifying protein 1

Sortilin-related VPS10 domaincontaining receptor 2

MAP/microtubule affinityregulating kinase 4

**Downregulated genes**

5-hydroxytryptamine (serotonin) receptor 6, G protein–coupled

Calcium channel, voltagedependent, beta 4 subunit

*Genes with modulated expression.*

receptor OPTN as well as MAOA/MAOB and CAV1.

#### *Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer… DOI: http://dx.doi.org/10.5772/intechopen.80981*

neurobiology and cancer metastasis. Thus, from ca. 30,000 genes, as found in a microarray experiment, 14 genes were selected as most promising. They are shown in **Table 1**. Data describing these genes are retrieved from the NCBI database [54].

From this list, some genes attracted our attention, including the autophagy receptor OPTN as well as MAOA/MAOB and CAV1.

What attracted our interest in this group of genes was that they share certain roles in cancer and neurology, and some were reported to have some direct or indirect link to autophagy.

The overexpression of the well-known mitochondrial enzyme MAOA, linked with many psychiatric illnesses, was shown to be associated with prostate cancer. MAOA caused neuroendocrine differentiation of prostate cancer cells through


#### **Table 1.**

*Genes with modulated expression.*

*Gene Expression and Control*

also in other cancers [43–48].

responsiveness to treatment [44].

an outcome of α7nAchR regulation [51].

**reference to autophagy**

kinase 1 (TBK1) as an important protein in both sporadic and familial ALS. TBK1 phosphorylates OPTN [40], and it was reported that a mutation of OPTN is also associated with ALS [41]. Furthermore, neuron-specific Atg5 and Atg7 knockout mice are associated with motor defects [42]. Beclin-1, the major player in the autophagic initiation process, has been shown to promote ALS by interacting with superoxide dismutase 1 (SOD1) and its downregulation was associated with aggregation of amyloid-β tau tangles, which are indicators of Alzheimer's disease (AD).

**3. Link between autophagy and the nicotinic cholinergic system**

The role of neurology genes in the progression and metastasis of cancer in general has been emphasized recently. In many reviews, Hildegard M. Schuller established the theory that modulation of the autonomic nervous system is responsible for driving cancer development, progression, and resistance to chemotherapy not only in non–small-cell lung cancer and pancreatic ductal adenocarcinoma but

She anticipated the different modifiable risk factors of PDAC development, including smoking, chronic psychological stress, and habitual ingestion of alcohol, to act mostly via the sensitization (α7nAChR) and desensitization (α4nAChR) of nAChRs that drive the expression of proteins, which regulate the synthesis and release of catecholamines and GABA and result in the hyperactivity of Gs-mediated cAMP signaling [47]. α7nAChR activation is responsible for the production of stress neurotransmitters, which are known to promote cancer features, as well as of serotonin, dopamine, and glutamate, while the desensitization of α4nAChR is the main reason for reduced GABA levels, which is known to be a protective neurotransmitter [45]. This is believed to disturb the normal equilibrium and homeostasis of the signaling neurotransmitters in favor of cancer development, progression, and reduced

A link between the nicotinic cholinergic system and autophagy can be thought as follows: in one study, nicotine hindered the macrophage clearance of mycobacterium tuberculosis via inhibition of autophagosome formation in infected T helper cells and macrophages [49]. In another study, nicotine enhanced the proteasome activity and the total protein ubiquitination as well as autophagy as was proven by the occurrence of autophagic vacuoles and increased MAP LC3-II at protein level. These mechanisms help in the downregulation of connexin 43 and limit the communication in endothelial cells based on the involvement of nAChR α4β2 and α3β2, but not α7 [50]. Jeong et al. have shown that melatonin's neuroprotective effects against prion-mediated neural damage are owing to the activation of autophagy as

**4. Modulated expression of some neurologic genes in PDAC with special** 

Our lab has identified a group of genes, which are modulated during pancreatic cancer liver metastasis [52]. The microarray data are derived from ASML rat PDAC cells that were reisolated from rat liver after they had been implanted intraportally and colonized the rat liver for various periods of time. These genes were arranged according to their fold change versus control cells (more than threefold modulation of expression) at early, intermediate, advanced, and final stages of metastasis, and the resulting genes were investigated by the Ingenuity Pathway Analysis program [53]. Among these genes, a subgroup was identified to have a dual role in

**46**

activation of autophagy, ROS production, and downregulation of repressor element-1 silencing transcription factor (REST) [55].

However, at mRNA level, MAOA was not measurably expressed in our panel of human PDAC cell lines. Another aspect, which prevented further experiments, was that the irreversible MAOA-inhibiting drug clorgyline halted the proliferation of BXPC3 cells only at very high concentrations, which rendered further studies of this gene unpromising.

Deficiency of the caveolae protein CAV1 stimulates the basal and inducible autophagy as a cell survival mechanism under starvation. This is a recently described function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy [56]. Another study reported that CAV1 regulates autophagy positively under oxidative stress and cerebral ischemic injury. CAV1 deficiency limited localization of Beclin-1 (BECN1) to the mitochondria and eliminated LC3 foci formation in response to hydrogen peroxide in the brain of CAV1 knockout mice [57]. CAV1 is related to tumorigenesis and metastasis. CAV1 overexpression in PDAC is associated with poor clinical outcome, as well as chemo- and radioresistance [58]. Moreover, signs of premature neuronal aging and degeneration are evident in CAV1 knockout mice together with increased Aβ, P-tau, and astrogliosis [59].

The gene optineurin (OPTN), which is an autophagy receptor, was also among the genes listed in **Table 1**. Since OPTN has an important role in many neurodegenerative diseases as well as a function as an autophagy receptor, thus linking autophagy in cancer and neurodegenerative diseases, a comprehensive overview of this gene is given as well as an outline of the expression of other autophagy genes in PDAC.

## **5. Optineurin**

OPTN is linked to many neurodegenerative diseases including normal tension glaucoma, primary open-angle glaucoma [60], as well as amyotrophic lateral sclerosis [41].

The OPTN gene is located on chromosome 10p13 and translates into a protein of 67-kDa. The mRNA consists of 16 exons; the first 3 are noncoding, while the coding exons give rise to a protein composed of 577 amino acids [61, 62]. OPTN was found to be head to head oriented with the gene coiled-coil domain containing 3 (CCDC3) with a distance of about 98-kb between their 5'UTRs [63]. OPTN has a half-life of around 8 h and its degradation engages the ubiquitin proteasomal system as its level increases following exposure to a proteasome inhibitor, but not to autophagic or lysosomal inhibitors [64].

OPTN encompasses several domains: an NF-κB-essential molecule-like domain, leucine zipper motif, coiled-coil motifs, an ubiquitin-binding domain (UBD), an LC3 interacting region, and a carboxyl (C)-terminal C2H2 type of zinc finger [65, 66].

As a cytoplasmic protein [60], OPTN colocalizes together with myosin VI and Rab8 around the Golgi complex and in vesicles at the plasma membrane [67]. It shows a high level of expression in certain tissues such as retina, brain, heart, skeletal muscle, placenta, testis, and kidney [68].

It interacts with itself to form homo-oligomers [69] and also with other molecules such as Ras-related protein 8 (Rab8) [70], huntingtin [71], myosin VI [72], transferrin receptor [68], LC3/GABARAP [62], polo-like kinase 1 [73, 74], TBK1 [75], as well as metabotropic glutamate receptor, transcription factor IIIA, serine/threonine kinase receptor-interacting protein 1, CYLD lysine 63 deubiquitinase (cylindromatosis, CYLD), and HECT (homologous to the E6-AP carboxyl terminus) domain and ankyrin

**49**

**Figure 2.**

*Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer…*

activity is increased with enhanced interferon production [76].

repeat containing E3 ubiquitin protein ligase 1 (HACE1) [65]. The structure of OPTN

OPTN plays different roles under physiological conditions including membrane trafficking, maintenance of the Golgi apparatus, exocytosis, protein secretion, cell division control, regulation of NF-κB, and host defense against pathogens [61, 62, 65, 67]. Its antiviral preventive response was based on its ability to regulate the interferon response in a cell cycle–dependent manner owing to its nuclear translocation together with deubiquitinating enzyme CYLD during the G2/M phase of the cell cycle, which abolishes the inhibitory effect it exerts on TBK1. As a result, the TBK1

The overexpression of OPTN was demonstrated to be protective against H2O2 mediated cell death, a function, which is compromised by a mutated form of OPTN (E50K), resulting in cells that are less fit to survive under stress conditions [70]. Beside all the above stated roles, OPTN is considered as a disease-linked gene. Mutations of OPTN or its altered expression are associated with multiple diseases including normal tension glaucoma and primary open-angle glaucoma [60] as well as plenty of neurodegenerative diseases including amyotrophic lateral sclerosis [41], ubiquitin-positive intraneuronal inclusions in ALS with dementia, basophilic inclusions in the basophilic type of ALS, neurofibrillary tangles and dystrophic neurites in Alzheimer's disease, Lewy bodies and Lewy neurites in Parkinson's disease, ballooned neurons in Creutzfeldt-Jakob disease, glial cytoplasmic inclusions in multiple system atrophy, and Pick bodies in Pick's disease with unknown significance [77]. Reduced OPTN expression in humans might increase the risk of developing Crohn's disease [78] and dispose to the occurrence of Paget's disease by enhancing osteoclast differentiation, as OPTN is a recently identified regulator of

The OPTN protein was identified as a selective autophagy receptor such as the multidomain scaffold/adaptor protein p62/sequestosome-1 (p62/SQSTM-1) and nuclear domain 10 protein 52 (NDP52) in terms of binding to polyubiquitinated cargoes and brings them to autophagosomes via its LC3-interacting region [65, 80–82]. In this context, it can help cells to get rid of pathogens as salmonella [80], defective mitochondria [82], and misfolded protein aggregates [83] or can have a

The role of OPTN in autophagy can also be independent from ubiquitination [65], where it can distinguish several protein aggregates through its C-terminal

*Graphic illustration of OPTN structural domains and the localization of these domains relative to its amino* 

*DOI: http://dx.doi.org/10.5772/intechopen.80981*

and some interactions are shown in **Figure 2**.

bone resorption [79].

role in tumor suppression [81].

*acid sequence as well as some of its interacting proteins.*

coiled-coil domain [84].

#### *Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer… DOI: http://dx.doi.org/10.5772/intechopen.80981*

repeat containing E3 ubiquitin protein ligase 1 (HACE1) [65]. The structure of OPTN and some interactions are shown in **Figure 2**.

OPTN plays different roles under physiological conditions including membrane trafficking, maintenance of the Golgi apparatus, exocytosis, protein secretion, cell division control, regulation of NF-κB, and host defense against pathogens [61, 62, 65, 67].

Its antiviral preventive response was based on its ability to regulate the interferon response in a cell cycle–dependent manner owing to its nuclear translocation together with deubiquitinating enzyme CYLD during the G2/M phase of the cell cycle, which abolishes the inhibitory effect it exerts on TBK1. As a result, the TBK1 activity is increased with enhanced interferon production [76].

The overexpression of OPTN was demonstrated to be protective against H2O2 mediated cell death, a function, which is compromised by a mutated form of OPTN (E50K), resulting in cells that are less fit to survive under stress conditions [70].

Beside all the above stated roles, OPTN is considered as a disease-linked gene. Mutations of OPTN or its altered expression are associated with multiple diseases including normal tension glaucoma and primary open-angle glaucoma [60] as well as plenty of neurodegenerative diseases including amyotrophic lateral sclerosis [41], ubiquitin-positive intraneuronal inclusions in ALS with dementia, basophilic inclusions in the basophilic type of ALS, neurofibrillary tangles and dystrophic neurites in Alzheimer's disease, Lewy bodies and Lewy neurites in Parkinson's disease, ballooned neurons in Creutzfeldt-Jakob disease, glial cytoplasmic inclusions in multiple system atrophy, and Pick bodies in Pick's disease with unknown significance [77]. Reduced OPTN expression in humans might increase the risk of developing Crohn's disease [78] and dispose to the occurrence of Paget's disease by enhancing osteoclast differentiation, as OPTN is a recently identified regulator of bone resorption [79].

The OPTN protein was identified as a selective autophagy receptor such as the multidomain scaffold/adaptor protein p62/sequestosome-1 (p62/SQSTM-1) and nuclear domain 10 protein 52 (NDP52) in terms of binding to polyubiquitinated cargoes and brings them to autophagosomes via its LC3-interacting region [65, 80–82]. In this context, it can help cells to get rid of pathogens as salmonella [80], defective mitochondria [82], and misfolded protein aggregates [83] or can have a role in tumor suppression [81].

The role of OPTN in autophagy can also be independent from ubiquitination [65], where it can distinguish several protein aggregates through its C-terminal coiled-coil domain [84].

#### **Figure 2.**

*Gene Expression and Control*

gene unpromising.

and astrogliosis [59].

**5. Optineurin**

sclerosis [41].

lysosomal inhibitors [64].

skeletal muscle, placenta, testis, and kidney [68].

activation of autophagy, ROS production, and downregulation of repressor ele-

Deficiency of the caveolae protein CAV1 stimulates the basal and inducible autophagy as a cell survival mechanism under starvation. This is a recently described function of CAV1 and lipid rafts in breast cancer development via

modulation of lysosomal function and autophagy [56]. Another study reported that CAV1 regulates autophagy positively under oxidative stress and cerebral ischemic injury. CAV1 deficiency limited localization of Beclin-1 (BECN1) to the mitochondria and eliminated LC3 foci formation in response to hydrogen peroxide in the brain of CAV1 knockout mice [57]. CAV1 is related to tumorigenesis and metastasis. CAV1 overexpression in PDAC is associated with poor clinical outcome, as well as chemo- and radioresistance [58]. Moreover, signs of premature neuronal aging and degeneration are evident in CAV1 knockout mice together with increased Aβ, P-tau,

The gene optineurin (OPTN), which is an autophagy receptor, was also among the genes listed in **Table 1**. Since OPTN has an important role in many neurodegenerative diseases as well as a function as an autophagy receptor, thus linking autophagy in cancer and neurodegenerative diseases, a comprehensive overview of this gene is given

OPTN is linked to many neurodegenerative diseases including normal tension glaucoma, primary open-angle glaucoma [60], as well as amyotrophic lateral

The OPTN gene is located on chromosome 10p13 and translates into a protein of 67-kDa. The mRNA consists of 16 exons; the first 3 are noncoding, while the coding exons give rise to a protein composed of 577 amino acids [61, 62]. OPTN was found to be head to head oriented with the gene coiled-coil domain containing 3 (CCDC3) with a distance of about 98-kb between their 5'UTRs [63]. OPTN has a half-life of around 8 h and its degradation engages the ubiquitin proteasomal system as its level increases following exposure to a proteasome inhibitor, but not to autophagic or

OPTN encompasses several domains: an NF-κB-essential molecule-like domain, leucine zipper motif, coiled-coil motifs, an ubiquitin-binding domain (UBD), an LC3 interacting region, and a carboxyl (C)-terminal C2H2 type of zinc finger [65, 66].

As a cytoplasmic protein [60], OPTN colocalizes together with myosin VI and Rab8 around the Golgi complex and in vesicles at the plasma membrane [67]. It shows a high level of expression in certain tissues such as retina, brain, heart,

It interacts with itself to form homo-oligomers [69] and also with other molecules such as Ras-related protein 8 (Rab8) [70], huntingtin [71], myosin VI [72], transferrin receptor [68], LC3/GABARAP [62], polo-like kinase 1 [73, 74], TBK1 [75], as well as metabotropic glutamate receptor, transcription factor IIIA, serine/threonine kinase receptor-interacting protein 1, CYLD lysine 63 deubiquitinase (cylindromatosis, CYLD), and HECT (homologous to the E6-AP carboxyl terminus) domain and ankyrin

as well as an outline of the expression of other autophagy genes in PDAC.

However, at mRNA level, MAOA was not measurably expressed in our panel of human PDAC cell lines. Another aspect, which prevented further experiments, was that the irreversible MAOA-inhibiting drug clorgyline halted the proliferation of BXPC3 cells only at very high concentrations, which rendered further studies of this

ment-1 silencing transcription factor (REST) [55].

**48**

*Graphic illustration of OPTN structural domains and the localization of these domains relative to its amino acid sequence as well as some of its interacting proteins.*

The role of OPTN in autophagy extends beyond being an autophagy receptor, as OPTN also plays a role as an autophagy inducer. Overexpression of OPTN in its wild type or mutated E50K forms, or its upregulation by cytokine treatment, was linked to elevated LC3-II levels in retinal ganglion cells, while the level of the proteasome activity marker PSMB5 (proteasome regulatory β 5) was reduced denoting induction of autophagy [64]. In vivo results confirmed the induction of autophagy and the reduction of ubiquitin proteasome pathway upon the injection of wild type and E50K OPTN transfected vectors in rat eyes [85].

Mutation or altered expression of OPTN may result in many diseases as glaucoma, ALS, other neurodegenerative diseases [65], or even cancer [81] owing to the implication of mitochondrial dysfunction and protein aggregation [65]. Mutations in both autophagy receptors p62 and OPTN in Paget's disease of the bone may attribute to an autophagy-related mechanism of developing this disease [65].

An overview of the RNA-seq data generated by the Cancer Genome Atlas (TCGA) revealed high expression of the OPTN gene across several cancer types (reported as median number fragments per kilo-base of exon per million reads (FPKM)) and was based on mRNA expression in cancer tissues (see **Figure 3**). In this regard and with data retrieved from the Protein Atlas website [86, 87], pancreatic cancer represents the tumor with the second highest OPTN expression and is topped only by renal cancer.

Prompted by this result, we analyzed the expression of autophagy genes and autophagy receptors in PDAC in a TCGA cohort with a sample size of 179. Most of the autophagy genes were above average genomic expression, represented by >7.5 log2 rsem (RNA-seq by expectation maximization) except for ATG10, which was below average. OPTN was second highest expressed of all autophagy genes, preceded only by SQSTM1 (**Figure 4**).

Based on these findings, we reasoned that OPTN might be involved in important mechanisms associated with cancer as well as with neurodegenerative diseases that require further analysis.

#### **Figure 3.**

*Overview of the RNA-seq data in TCGA of 17 cancer cohorts showing the highest OPTN expression in renal cell carcinoma followed by PDAC (expressed in terms of median FPKM) [86–88].*

**51**

**6. Conclusions**

**Figure 4.**

further studies to be properly delineated.

The authors have no conflicting interests.

**Acknowledgements**

Austauschdienst (DAAD).

**Conflict of interest**

*Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer…*

In summary, autophagy represents a link between the nervous system and cancer in general as well as pancreatic cancer in particular. The modulated expression of autophagy-related genes in cancer and neurodegenerative diseases highlights the importance of this mechanism and suggests further studies on their regulation and effective targeting. Autophagy is a new background for certain genes in cancer as well as in neurology, and understanding this process may well serve as a platform for understanding the pathogenesis of these diseases in different organs. In addition, there seems to be a special role for OPTN in different neurodegenerative diseases as well as cancer and this protein could well be a target in cancer treatment. The link between nicotinic acetylcholine receptors and autophagy still requires

*Expression of autophagy-related genes and receptors in a PDAC cohort with a sample size of 179 patients* 

*showing high expression of all autophagy-related genes (> 7.5 log2 rsem) except for ATG10.*

The authors express their gratitude to Dr. Ashwini K. Sharma for the generation of **Figure 4** and his continuous support with questions related to bioinformatics. Doaa M. Ali was supported by a PhD Grant from the Deutscher Akademischer

*DOI: http://dx.doi.org/10.5772/intechopen.80981*

*Autophagy-Related Gene Expression Changes Are Found in Pancreatic Cancer… DOI: http://dx.doi.org/10.5772/intechopen.80981*

#### **Figure 4.**

*Gene Expression and Control*

disease [65].

cancer.

E50K OPTN transfected vectors in rat eyes [85].

ceded only by SQSTM1 (**Figure 4**).

require further analysis.

The role of OPTN in autophagy extends beyond being an autophagy receptor, as OPTN also plays a role as an autophagy inducer. Overexpression of OPTN in its wild type or mutated E50K forms, or its upregulation by cytokine treatment, was linked to elevated LC3-II levels in retinal ganglion cells, while the level of the proteasome activity marker PSMB5 (proteasome regulatory β 5) was reduced denoting induction of autophagy [64]. In vivo results confirmed the induction of autophagy and the reduction of ubiquitin proteasome pathway upon the injection of wild type and

Mutation or altered expression of OPTN may result in many diseases as glaucoma, ALS, other neurodegenerative diseases [65], or even cancer [81] owing to the implication of mitochondrial dysfunction and protein aggregation [65]. Mutations in both autophagy receptors p62 and OPTN in Paget's disease of the bone may attribute to an autophagy-related mechanism of developing this

An overview of the RNA-seq data generated by the Cancer Genome Atlas (TCGA) revealed high expression of the OPTN gene across several cancer types (reported as median number fragments per kilo-base of exon per million reads (FPKM)) and was based on mRNA expression in cancer tissues (see **Figure 3**). In this regard and with data retrieved from the Protein Atlas website [86, 87], pancreatic cancer represents the tumor with the second highest OPTN expression and is topped only by renal

Prompted by this result, we analyzed the expression of autophagy genes and autophagy receptors in PDAC in a TCGA cohort with a sample size of 179. Most of the autophagy genes were above average genomic expression, represented by >7.5 log2 rsem (RNA-seq by expectation maximization) except for ATG10, which was below average. OPTN was second highest expressed of all autophagy genes, pre-

Based on these findings, we reasoned that OPTN might be involved in important mechanisms associated with cancer as well as with neurodegenerative diseases that

*Overview of the RNA-seq data in TCGA of 17 cancer cohorts showing the highest OPTN expression in renal* 

*cell carcinoma followed by PDAC (expressed in terms of median FPKM) [86–88].*

**50**

**Figure 3.**

*Expression of autophagy-related genes and receptors in a PDAC cohort with a sample size of 179 patients showing high expression of all autophagy-related genes (> 7.5 log2 rsem) except for ATG10.*

#### **6. Conclusions**

In summary, autophagy represents a link between the nervous system and cancer in general as well as pancreatic cancer in particular. The modulated expression of autophagy-related genes in cancer and neurodegenerative diseases highlights the importance of this mechanism and suggests further studies on their regulation and effective targeting. Autophagy is a new background for certain genes in cancer as well as in neurology, and understanding this process may well serve as a platform for understanding the pathogenesis of these diseases in different organs. In addition, there seems to be a special role for OPTN in different neurodegenerative diseases as well as cancer and this protein could well be a target in cancer treatment. The link between nicotinic acetylcholine receptors and autophagy still requires further studies to be properly delineated.

#### **Acknowledgements**

The authors express their gratitude to Dr. Ashwini K. Sharma for the generation of **Figure 4** and his continuous support with questions related to bioinformatics. Doaa M. Ali was supported by a PhD Grant from the Deutscher Akademischer Austauschdienst (DAAD).

#### **Conflict of interest**

The authors have no conflicting interests.
