Cancer is a rampant big health problem still counted as a decisive factor in ascending mortality worldwide [22]. Hence, despite the extensive survey, the exact mechanisms involved are hitherto rudimentary. However, considering the upward mobility of state-of-the-art equipment in the biological subject alongside the myriad generated big data in this area, re-analyzing the pre-existed datasets and integrating the kinds of the biological layer could be a promising approach to catch a comprehensive insight into the underlying mechanisms of complex disorders [23, 24].
Accordingly, in this study, a protein expression profile of individuals’ colorectal tumor tissue compared to non-tumor tissue reported by Costanza et al. was analyzed after validating the satisfying quality of the dataset; a bunch of differentially expressed proteins was detected to perform valuable further analysis. Since the crucial role of integrative measures in the complex disorder examination, an inclusive map comprised of DEPs, miRNAs, and lncRNAs was created to facilitate our understanding of the pathogenesis of CRC advancement, which could provide an opportunity to announce novel drug targets and remedial approaches. In the first step, various enrichment measures were carried out to overview the altered biomedical phenomena comprehensively. In accordance with the achieved findings, all results in these methods consistently revealed the critical roles of mRNA processing and immune response in the pathogenesis of CRC. Accordingly, a large body of evidence has indicated the pivotal function of mRNA processing, such as alternative splicing (AS), in CRC progression. It is also worth mentioning that AS events could be considered potential therapeutic targets for CRC. In this regard, the increased expression of COL6A3 as a survival element in CRC has been recently reported [25]. Remarkably, our result in network analysis revealed SF3B3 as the highest-scoring central protein known as the main splicing element in the mRNA splicing pathway, which has not yet been investigated in CRC advancement. However, a recent study has merely highlighted SF3B3 as an age-associated factor in CRC advancement [26]. Among all the identified hub proteins, another involved splicing element such as HNRNPA1 and SRSF2 can be seen [27]. Accordingly, Karnni. et al. indicated that SRSF2 is a well-known mutated protein in some sort of cancer; also, it is shown that the alternative splicing in SRSF2 is directly associated with tumor development [28]; however, detailed function of the SRSF2 in CRC has not been previously shown. Further research should investigate splicing procedures, specifically hub proteins in CRC development, based on attained findings.
In line with previous studies, our results underscored the role of immune response pathways in CRC advancement. Among the enriched related terms, a wide variety of pathways can be seen which are practically linked to innate immune systems. For instance, platelet degranulation, which is examined in a recent study that demonstrated that depending on the ambiance of a function such as a bloodstream or local, could be a promotive or prophylactic factor in CRC development [29]. Notably, notwithstanding the pathway as mentioned earlier, our result revealed the alteration of neutrophil and interleukin terms, which is generally considered a pioneer factor in the inflammation response against infectious state and homeostasis regulation. Moreover, inconsistent with the pivotal role of the immune response, such as announced terms, GO analysis indicated coherent findings based on neutrophil and platelet degranulation, which can describe the inflammatory nature of cancer and their critical role in the wound healing process. Strictly speaking, it is recently considered that platelets play a predominant role in immune response regulation; more broadly, further research might be required to provide a comprehensive overview to introduce potential pertinent biomarkers [30].
The proportion of enriched terms among all observations is related to scavenger receptor function that is directly linked to innate immune response; accordingly, our results revealed scavenger receptor class A (SR-A1) as one of the essential pathways, which also accords with the earlier observations, which showed how the suppression of SR-A1 can mitigate lung cancer metastasis [3]. This finding corroborates the ideas of Song. Et.al suggested that all sorts of scavenger receptors such as A to E are principally related to an array of cancer [31]; however, it seems that further research is demanded to understand their role better so that they can be considered a rational remedial approach also potential biomarker.
To put it more simply, our functional analysis favors the modification of two main categories: mRNA processing and immune response and its proper functions like neutrophil and platelet degranulation; what is more, scavenger receptors could point to metastasis and wound healing processes in CRC. The engagement of immune systems may provide a novel insight into the immunological aspect of CRC pathogenesis and should be focused on further investigation.
In the following step, based on the constructed multi-layer network, topological parameters were screened to identify the central molecules in each predicted layer in order to decipher the critical driver of pathogenesis in CRC. Hence, given the pivotal role of regulatory factors such as miRNAs and lncRNAs, an interacting multi-layer map could be a reasonable measure to decipher the complex nature of a cellular regularity procedure. Despite the introduced hub DEPs, which show that a considerable part of them are in line with our functional analysis, we recognize hub regulatory elements; interestingly, the majority of central miRNAs have been previously examined as decisive elements either in CRC progression or metastasis and apoptotic function, like miR-15b-5p, which has just been recently introduced as a promotive factor for growth and apoptosis in breast and CRC [32]. Consequently, other identified hub-miRNAs, including miR-16-5p, miR-424-5p, miR-497-5p, and let-7b-5p, have been shown in the initial investigation that agrees with their influential role as a progressive factor in various sorts of cancer [33, 34]. Although it could be noted that some of the recognized hubs have not been directly investigated in CRC advancement, likewise miR-1301-3p, therefore, since miRNAs could be an effective leader in certain kinds of specific biological processes, focusing on them can facilitate our understanding of underlying pathogenesis mechanisms, and what is more, provide potential biomarkers. Passing on to the constructed interacting network, another predicted regulative factor is associated with lncRNAs, which possess an outstanding possible function in pre-and post-translational regulation and could occasionally affect miRNAs. Therefore, their influential role has been proposed in several kinds of research. Among all the identified hub-lncRNAs, disregarding the well-known RNA molecules in CRC pathogenicity, some have not been examined directly in the progression of CRC, including NUTM2B-AS1, LINC00943, MCM3AP-AS1 (C1orf132), and SLC9A3-AS1. LINC00943, as an intergenic RNA, was announced as one of the central lncRNAs shown in the former studies as an influential regulatory factor in malignant tumors and also identified and validated as a potential remedy in melanoma malignancy [35].
Moreover, SLC9A3-AS1 is an antisense RNA 1 involved in several orders through the affection of proteins and other regulatory factors like miRNAs in facilitating nasopharyngeal carcinoma [36]. Remarkably, according to the substantial effect of SLC9A3-AS1 in the immune response-related pathways, complications can be considered potential targets in CRC progression. Therefore, further studies, which take these regulatory elements into account, will need to be undertaken so as to deepen our understanding of the CRC pathogeny mechanisms.