Roles of non-coding RNAs in cell death pathways involved in the treatment of resistance and recurrence of cancer

Data provided by the Global Burden of Diseases, Injuries, and Risk Factors Study has shown the presence of 2·88 million and 1·58 million risk-attributable cancer deaths in males and females, respectively [77]. Cancer initiation is regarded as a multi-stage process in which normal cells grow and divide out of control as a result of breaking down the normal process of cell proliferation. Several factors such as becoming insensitive to growth restriction signals, avoiding apoptosis, tissue invasion and metastasis are associated with malignant growth and uncontrolled cell division [2], [17]. Although several types of treatments including surgery, radiation therapy, chemotherapy, and gene therapy are used to stop tumor growth, cancer cells have the capability of resistance to many different types of treatments. Excess efflux of drug, boosted repair/increased tolerance to DNA damage, high anti-apoptotic potentials, and enzymatic deactivation permit cancer cell to survive the therapy. Although these tumor treatments can lead to the cell death in most tumors, in some cases tumor cells survive and regrow. Since, some living cancer cells have the capability of staying alive, they can remain on the same part or spread to different parts of the body. This is called cancer recurrence. As the primary cancer cells remain in small part, which is undetectable with tests, after a while they undergo genetic modifications, tumor cells relapse and cancer return after treatment. This can be occurred after weeks, months or even years after primary cancer establishment [89].

One reason for cancer recurrence is that the original treatment did not eliminate all cancer cells and cancer cells resisting to treatments such as chemotherapy and radiotherapy will survive and give rise to a new tumor. Moreover, some cancer cells spread to other parts of the body and gradually grow there to form a tumor [2]. Drug resistance is the most important factor in cancer recurrence that can result in the treatments failure which is the most prominent cancer mortality factor [58].

Different mechanisms can explain molecular base of drug resistance and treatment failure. Resistance can be the consequence of genetic differences in patients’ tumors. Recently, it has been shown that chemotherapy resistance correlates with the quiescence phase of cancer stem cells and epithelial-mesenchymal transition (EMT) mechanism. Expression of energy dependent transporters which expel anti-cancer drugs is the common mechanism of resistance. Drug intoxication induction, decreased sensitivity to apoptotic signals, and cell death pathways inactivation result in drug resistance in cancer cells. From the other side, recent studies have demonstrated strong relation between drug resistance phenotype and epigenetic modifications in cancer cells [58]. Furthermore, one of the major gene expression regulators in epigenetic, transcription and after transcription stage are non-coding RNAs (ncRNAs) that play a role in chemotherapy resistance through cell cycle regulation such as keeping cell in relax state, apoptosis inhibition and increasing repair of damaged DNA.

NcRNAs constitute the main part (98%) of the transcriptome, and several different classes of regulatory RNAs with important functions are being identified. One of the problems that researchers face is identifying the role and function of this part of transcriptome, and the non-coding RNAs within it represent a gold mine of potential new biomarkers and drug targets.

Most abundant and important RNAs such as tRNAs, rRNAs, snoRNAs, snRNAs, siRNAs, piRNAs, microRNAs (miRNAs) and long ncRNAs (lncRNAs) are famous non-coding RNAs. Non-coding RNAs involve in all development stages like stem cells regulations, transferring genetic reservoirs, cell development, positioning of cellular particles and deciding cell death. They accomplish these tasks by transcription and after transcription regulation and mostly by epigenetic mechanisms like histone modification, DNA methylation or direct targeting of RNAs and disrupting or inactivating them [14]. So, it is undoubtable that dysregulation and unsound function adjustment can be associated with human diseases such as cancer. Recent studies have shown that different ncRNAs such as miRNAs and lncRNAs have a role in the development and recurrence of different cancers. But their concise action is unclear [9], [38]. Altogether, cancer cells would be immortal and resist to different treatments and the final repercussion is persistence to cell death. Regarding the important role of ncRNAs and cell death pathways in treatment resistance and tumor recurrence, investigation of the role of these RNAs in various cell death pathways is important. This might lead to find more efficient treatments in the future.

In the middle of various cell death paths including apoptosis, necrosis, autophagy, cell senescence, anoikis and necrosis, there are three main routes needed to be controlled precisely.

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