ABERRANT miRNA IN PANCREATIC CANCER

The world’s 10th most crucial malignancy is pancreatic cancer. The most frequent pancreatic cancer detected in the exocrine pancreas composite is pancreatic ductal adenocarcinoma (PDAC). In developing nations, it is often diagnosed, and in males, it is more common than in women[1]. Patients with pancreatic cancer have a ~1 percent survival rate at five years, mainly because of difficulties in the detection of early-stage pancreatic cancer[1][2][3]. Around 280,000 new cases are worldwide diagnosed with pancreatic cancer every year[1]. Risk factors are the most common. Smoking, diabetes, hereditary pancreatitis, multiple type 1 endocrine neoplasia syndrome, hereditary nonpolyposis of the colon cancer, Hippel-Lindau syndrome, telangiectasia and family atypical multiple mole melanoma syndromes (FAMMM) are most commonly associated with the development of pancreatic cancer[4].

Early diagnosis of pancreatic cancer enhances the chance of a better outcome, as do numerous other malignancies. Pancreatic cancer is complicated to detect and diagnose since it shows no particular, detectable symptoms and hides behind larger abdominal organs[5].

New hopes for improving pancreatic cancer treatment are linked with genetic testing of microRNA (miRNA) expression changes, which aims to understand better pathogenesis and diagnostic and therapeutic possibilities[6]. A wide range of data has shown that in serum and cancer tissues, microRNAs are aberrantly expressed and cause oncogenic or tumour suppressing activities[6].

miRNA

Non-coding RNAs, which control gene expression by mRNA degradation or inhibition, are a subfamily of MicroRNAs[7].

miRNAs belong to a cellular regulatory network that regulates numerous biological essential activities, including cell growth, proliferation, distinction, development and apoptosis[1]. It functions as tumour suppressors or oncogenes, miRNAs function[1].

Moreover, miRNAs are potential indicators of diagnosis and prognoses for human illnesses, including pancreatic cancer[1]. They are more stable than protein and present in most biological fluids (i.e., blood, amniotic fluid, breast milk, bronchial lavage, cerebral fluid (CSF), colostrum, peritoneal fluid, pleural fluid, saliva and urine)[1]. Biomarker identification in organic fluids is especially intriguing, as this provides a fast, non-invasive, and very affordable approach to illness detection and diagnosis[1]. For early diagnosis, therapy and prognosis of pancreatic cancer, it would be helpful to identify a particular miRNA profile in bodily fluids[1]. Various miRNAs have been found to play an essential role in pancreatic cancer regulation by affecting the growth, development, invasion, metastasis and treatment resistance[1].

Oncogenes and genes that suppress tumours are usually regulated to the optimum balance of activation/inhibition[7]. When the downregulation of a certain miRNA occurs, it promotes the oncogene activity, a tumour suppressor miRNA[7]. On the other hand, if the oncomiR is upregulated, the target tumour suppressor gene will continue to be inhibited[7]. The outcome is a lack of control over the particular routes of tumour development[7]. Deregulation will lead to tumour growth by any of the miRNA types[7].

ABERRANT miRNA EXPRESSION PATTERN IN PANCREATIC CANCER 

Patterns of miRNA expression differ considerably between cancer types; hence, miRNA expression patterns might be utilized as potential non-invasive diagnostic indicators[7]. Some of the aberrant miRNAs identified by research might play a key role in PDAC genesis and metastasis[2]. MiR-221 over-expression can be necessary for the platelet-derived growth factor (PDGF) driven phenotypic migration, and proliferation of pancreatic cancer cells (PDGF)[2]. Furthermore, miRNA profiling should have an advantage over using mRNA profiles to represent many more reliable targets[7]. Identifying a small number of miRNAs has been more reliable than the data from 16,000 mRNAs with a more robust hierarchical clustering[7]. There were various miRNA expression profiles in pancreatic cancer, forming a miRNANome between the normal and malignant pancreas[7]. These miRNA expressions were determined by several gene profiling techniques, primarily utilizing micro-arrays, RNA-sequencing, and RT-PCR analysis[7]. Because of the stable circulation of miRNA, blood screenings might be used to detect particular miRNAs related to the stage, survival or disease aggression[7].

miRNA AS THERAPEUTIC TARGET IN PDAC

Gemcitabine, which has a modest tumour suppression response rate of about 12 per cent, is utilized in most chemotherapy treatments for pancreatic cancer[1]. Therefore, it is vital to find novel and improved treatments for pancreatic cancer[1]. The effectiveness of miRNA as a treatment strategy in managing PDAC has been proven by clinical trials[1]. Many miRNAs strongly downregulate PDAC-relevant genes and contribute to disease development[2]. Therefore chemically manipulated antisense oligonucleotide or ectopic expression of miRNA can be explored for treatment[2]. Since one miRNA may potentially influence multiple target genes, it presents exciting therapeutic opportunities for artificially boosting or reducing the expression signature of that miRNA[2].

Aberrant miRNA expression in PDAC impacts cancer suppressor genes oncogenically and causes subsequent effects on cell proliferation, death, and metastasis[2]. miR-96 binds directly to the oncogene of KRAS and can lower miR-96 ectopic expression in PDAC by reducing pancreatic cell proliferation, movement, and invasion, suggesting its therapeutic potential in PDAC[2]. Additional miRNAs, such as let 7, miR-21, miR-27a, miR-31, miR-200, and miR-221, can be utilized as new PDAC therapeutic agents, with the oncogenic activities or tumour suppressor functions[2].

miRNA AS A BIOMARKER FOR DIAGNOSIS OF PDAC

It is often known that PDAC is an insidious condition without certain early signs unless the primary tumour is situated in the head of the pancreas (obstructive jaundice)[2]. A larger interval between the origin of symptoms and the initial diagnosis of PDAC is linked with the disease being first recognized at a more advanced stage with a poor prognosis[2].

In instances in which PC surgical resection is the only curative therapy, identifying early biomarkers is crucial. Surgery is possible only in 15-20 percent of individuals with early PC diagnoses[7]. However, the postoperative complications linked with this surgery are common, and cases such as chronic pancreatitis or pancreatic tuberculosis are ordinarily hard to differentiate from cancer cases[7]. The antigen 19–9 (CA 19–9) serum carbohydrate has been utilized to evaluate clinical therapy effectiveness in pancreatic cancer[7]. Limitations such as inefficiency, lacking sensitivity and low specificity are linked with CA 19-9 however, it is still the sole marker approved by the FDA in pancreatic cancer[7]. Additional antigens, including CEA and CA125 as early indicators, were entirely inactive but were used as markers of therapy responsiveness by some oncologists[7]. Therefore, an early screening test might fulfil the PC diagnostic biomarker demand using discovered miRNAs[7]. The benefits of utilizing miRNAs include serum stability, easy non-invasive detection in circulation and a convenient screening technique[7].

miRNA IN PROGNOSIS OF PANCREATIC CANCER

The characteristic of the PDAC is poor survival[2]. The profiling of miRNAs by distinct illness features and stages of patient samples offers knowledge of miRNAs’ prognostic role[7].

Global miRNA microarray profiling may separate miRNA expression in normal vs pancreatic cancer tissues and serve as a potential prognostic predictor of disease[1]. The high miR-452, miR-102, miR-127, miR-518a-2, miR-187 and miR-30a-3p expressions were linked to the increase in over two-year survival rates[1]. Notably, unregulated levels of miRNAs, miR-21, miR-155, and miR-196a in plasma, and miR-141 in the sera were seen in pancreatic cancer patients who had a lower overall survival rate[1]. Moreover, another study also showed that in sera of PDAC patients, levels of miR-196a were raised in association with poor survival and advanced illness[1]. Furthermore, miR-196a expression was proposed as a more precise predictor of PDAC development[1]. Reduced survival is also related to overexpression of miR-196a-2 and miR-219. Median survival was 14.3 months for miR-196a-2 patients compared to 26.5 months for low expression individuals[1]. The mean survival was 13.6 months for miR-219 people compared to 23.8 months for low-expression patients[1]

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