LncRNA NNT-AS1/hsa-miR-485–5p/HSP90 axis in-silico and clinical prospect correlated-to histologic grades-based CRC stratification: A step toward ncRNA Precision

Colorectal cancer (CRC) is a heterogeneous malignancy that affects the colon and rectum [1]. It is the third most prevalent and lethal malignancy, with roughly 1.9 million new cases and nearly 9.4% of cancer-related deaths in 2020 worldwide [2]. The CRC survival rate mostly relies on the disease's stage at the time of diagnosis. Thus, early detection of CRC provides a higher 5-year survival probability of 80–90%, compared to just 14% in the late stage with distant metastases [3]. Colonoscopy is the gold standard method for CRC diagnosis [4]. Alongside its great accuracy, it is an invasive technique with considerable mortality risks, such as intestinal perforation and bleeding, limiting its usage for screening [5]. Fecal occult blood test, carbohydrate antigen 19–9 (CA19–9) and carcinoembryonic antigen (CEA) are the currently available CRC early diagnosis screening/ tumor markers (TMs) tests [6], [7]. Although CEA and CA19–9 tests are simple, non-invasive, affordable, and safe, their diagnostic accuracy is limited [8], [9]. Screening and early diagnosis for CRC have been identified as the most significant factor for lowering mortality [10].

Long non-coding RNA (lncRNA), which are more than 200 nucleotides non-coding RNAs (ncRNAs) [11], are either over-expressed or down-regulated in numerous malignancies, and act as potential molecular mediators for various tumors progression [12]. Overexpressed lncRNAs act as oncogenes [13] enhancing tumor cell proliferation [14], apoptosis [15], invasion [16], metastasis [17], and autophagy [18]. Several lncRNAs have been linked to the incidence, metastasis, and therapeutic resistance of CRC [19], [20], [21], [22]. Recent research suggested that the lncRNA Nicotinamide Nucleotide Transhydrogenase-antisense RNA1 (NNT-AS1), which is localized in the 5p12 human chromosome, is involved in gene expression regulation [23] and plays important roles in a variety of cancers, such as breast cancer [24], cervical cancer [25], hepatocellular carcinoma [26], and osteosarcoma [27], however, insufficient research was performed about lncRNA NNT-AS1 role in CRC [28].

MicroRNAs (miRNAs) are small ncRNAs with ∼22 nucleotides length [29], that undertake a variety of biological functions such as cell proliferation [30], apoptosis [31], and angiogenesis [32]. The mature miRNA species, also known as the miRNA-5p (guide’ strand) and − 3p species (passenger miRNA), can originate from both the 5′ and 3′ arms of the precursor duplex [33]. The arm that is destined to be loaded into the RNA-induced silencing complex is the guide strand [34]. Passenger miRNAs were assumed to be entirely destroyed, however, deep sequencing investigations have revealed that certain minor miRNAs retain and, in fact, play a meaningful role in gene regulation [35]. Numerous studies have found a substantial association between miRs dysregulation and tumor metastasis [36], [37], [38]. Homo sapiens (hsa)-miR-485–5p is located on the human chromosome 14q32 and has been identified as an anticancer/tumor suppressor gene in several human malignancies, through targeting and regulating the expression of downstream cell proliferation and invasion genes [39], [40]. The regulatory function of hsa-miR-485–5p in CRC is still undetermined.

LncRNAs-miRs interaction would control the incidence and/or progression of various cancer types [41], [42], [43], as well as being considered as potential target for future treatment invention. LncRNA NNT-AS1 was found to promote proliferation, migration, and invasion of cholangiocarcinoma via sponging hsa-miR-485. This sponging process elevated β-catenin and B-cell CLL/lymphoma 9 (BCL9) in response [44]. LncRNA NNT-AS1's relation to hsa-miR-485–5p in CRC remains to be determined clinically.

In most cells, under non-stress settings, heat shock protein 90 (HSP90) are highly conserved molecular chaperones that make up 1–2% of all cellular proteins. Important functions of HSP90 proteins include protein folding and degradation [45]. Physiologically, the molecular chaperone HSP90AB1 [46] interactions with other co-chaperones play a crucial part for folding of the newly generated proteins or in stabilizing and refolding denatured proteins following stress [47], but, pathologically, is involved in tumorigenesis [48]. For instance, within osteosarcoma, hsa-miR-485–5p binds to the 3′-untranslated region (UTR) of HSP90 messenger RNA (mRNA) to reduce HSP90 protein production, hence exerting a tumor suppressor effect [49]. Therefore, research is warranted to determine the clinical significance of the lncRNA NNT-AS1/hsa-miR-485–5p/HSP90 axis in CRC patients.

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