1. Please check and comment entries here.
Table of Contents

    Topic review

    PVT1: novel colorectal cancer biomarker

    View times: 127
    Submitted by: Olorunseun Ogunwobi

    Definition

    Colorectal cancer is a very deadly disease with a current lack of a reliable biomarker for early detection, non-invasive diagnosis, treatment, prognostication, and monitoring of treatment. This entry provides information that indicates that PVT1 is a novel biomarker in colorectal cancer. Further research is required to establish how this knowledge can be used for clinical applications.

    Colorectal cancer (CRC) is a leading cause of death worldwide, despite progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. Novel therapeutic agents have improved survival in both the adjuvant and advanced disease settings, albeit with an increased risk of toxicity and cost. However, metastatic disease continues to have a poor long-term prognosis and significant challenges remain due to late stage diagnosis and treatment failure. Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response. The past three decades have seen advances in genomics and molecular pathology of cancer biomarkers, allowing for greater individualization of therapy with a positive impact on survival outcomes. Clinically useful predictive biomarkers aid clinical decision making, such as the presence of KRAS gene mutations predicting benefit from epidermal growth factor receptor (EGFR) inhibiting antibodies. However, few biomarkers have been translated into clinical practice highlighting the need for further investigation. We review a range of protein, DNA and RNA-based biomarkers under investigation for diagnostic, predictive, and prognostic properties for CRC. In particular, long non-coding RNAs (lncRNA), have been investigated as biomarkers in a range of cancers including colorectal cancer. Specifically, we evaluate the potential role of lncRNA plasmacytoma variant translocation 1 (PVT1), an oncogene, as a diagnostic, prognostic, and therapeutic biomarker in colorectal cancer.

    1. Introduction: Epidemiology, Burden of Disease and Challenges in Treatment & Chemoresistance

      1.1. Epidemiology

     Colorectal cancer (CRC) is the fourth most common cancer overall worldwide contributing to 9.7% of global cancer burden [1][2][3][4][5]. It affects 746,000 men (10% of all cancer cases) and 614,000 women (9.2% of all cancer cases) with most cases (55%) occurring in developed countries [3][6]. Furthermore, in the UK, 42,300 new colorectal cancer cases are diagnosed each year making it the fourth most common cancer overall, and third most common in males and females [5]. In addition, the incidence of colorectal cancer increased between 1991 and 2016 and is attributed to lifestyle, environmental changes, and aging populations [7][8]. Although bowel cancer incidence has fallen in the UK in the past decade by 4%, the lifestyle risk factors remain. Moreover, the burden of CRC is expected to increase with 2.2 million new cases and 1.1 million deaths expected globally by 2030 [9]. In addition, significant challenges remain in managing disease burden. In England, five-year overall survival for CRC is 58.4% which is lower than the US reported 60–65% [10][11]. Moreover, US reported survival was static between 1996 and 2014 [10][11]. Further challenges remain due to the ageing demographic and advanced presentation of disease [12]. Older patients, above age 75 years, make up 44% of new colorectal cancer diagnoses and an estimated 20–25% of CRC is diagnosed at the metastatic stage with an additional 25% of patients developing metastasis during their illness [5][13]. As a result, CRC accounts for 8.5% of cancer related deaths worldwide with 16,300 deaths per year in the UK making it the second most frequent cause of cancer related deaths at 10%. Although survival is stage dependent with 92% survival for stage I, compared to 10% in stage IV, there has been an improvement in survival for the 60–69 year age group attributed to screening [5]. Thus, CRC remains a prevalent challenge in cancer management emphasizing the need for early diagnosis. 

    1.2. Screening Programs

    Declining mortality due to improvements has been shown with early detection through screening and effective treatment [14][15][16][17]. The UK CRC screening program relying on fecal detected occult blood (FOBT) and colonoscopy has led to 16% decline in overall mortality rate without affecting incidence [18]. However, FOBT has reduced sensitivity for advanced adenomas and CRC which may improve with newly implemented immunochemical testing (FIT) [19][20]. This screening test is offered in the UK every 2 years between 60–74 years with a one-off test aged 55 years [5]. These tests are precursors for more invasive colonoscopy to identify pre-malignant or malignant lesions. Furthermore, studies randomized trials have shown a reduction in CRC incidence up to 23% and CRC-related mortality by 31% using flexible sigmoidoscopy as a primary screening tool [21]. However, this remains an invasive and resource intensive technique. There is no universally agreed screening protocol for early disease stages, and significant variation remains. In addition, up to 70% of cancers presenting with symptoms are at an advanced stage [22]. This emphasizes the value of screening programs with early detection of pre-malignant or early stage (I-II) CRC leading to improved CRC survival, quality of life and disease-free outcomes. Moreover, screening for biomarkers at all stages, including diagnostic, prognostic, and predictive, may provide opportunities for targeted intervention to improve outcomes whilst reducing the risk of treatment toxicity [10][22].

    1.3. Current Treatment Effectiveness

    Treatment of CRC depends upon stage of disease according to the TNM classification, patient health, and curative versus palliative intent [12][23][24][25]. This comprises surgery, chemotherapy, and immunotherapy. Factors including stage, circumferential resection margin, lymphovascular invasion, perineural invasion, and genotyping are used to determine need for and type of adjuvant treatment [26][27]. Fluorouracil (5-FU), a fluoropyrimidine is used as part of the FOLFOX (Folinic acid + Oxaliplatin) or FOLFIRI (Folinic acid + Irinotecan) regimens leading to improved overall disease-free and progression-free survival in both advanced and metastatic disease [24][27][28][29]. However, 5-FU is associated with toxicity and reduced clinical response in patients with microsatellite instability (MSI) status as well as dihydropyrimidine dehydrogenase (DPYD) deficiency [30][31][32][33][34]. In addition, 5-FU leads to a modest 2–4% improvement in five-year disease free survival in stage II CRC [35]. However, previous studies have shown between 20–25% recurrence in treated Stage II lymph node negative colon cancer within five years [36][37]. In addition, the anti-EGFR cetuximab and anti-vascular endothelial growth factor receptor (VEGFR) bevacizumab response rate is higher in Kirsten rat sarcoma viral oncogene (KRAS) wildtype compared to KRAS mutants leading to its application in clinical practice [38][39]. Moreover, in metastatic CRC, the anti-programmed cell death receptor-1 agents Nivolumab and Ipilimumab have shown benefit in MSI and mismatch repair deficient genotypes thereby gaining approval in patients progressing on first line chemotherapy [40]. Further experimental treatments such as Regofarenib, an anti-angiogenic compound, shows poor overall survival in KRAS mutants but improved progression free survival in association with phosphorylated proline-rich protein kinase B (AKT) in metastatic CRC [41][42]. Thus, although the revised TNM application may lead to a reduction in over or undertreatment of CRC, the risks versus benefits of treatment selection need to be informed by molecular characteristics of individual tumors to develop personalized treatment, overcome poor efficacy and chemoresistance.

    2. Why Do We Need a Biomarker: The Role for Biomarkers in Early Detection of Colorectal Cancer

     Biomarkers are molecular patterns that can be used as a tool for early cancer detection and individualized CRC treatment [30][43][44]. They can be divided into diagnostic, prognostic, or predictive categories. Thus, biomarkers provide utility at different stages of the disease to determine disease progression, recurrence, as well as providing a personalized indicator for therapeutic effectiveness.

    Firstly, early diagnosis in asymptomatic patients remains a key target to achieve favorable survival outcomes through identification of early CRC as well as pre-malignant lesions including high risk polyps. The sensitivity for detecting CRC using current FIT testing (100ng/mL) is 73.8% versus 92.3% for a stool-based DNA assay screening KRAS, aberrant NDRG4 and BMP3 methylation [19]. Furthermore, FIT testing sensitivity for advanced precancerous lesions is 23.8% versus 42.4% with stool DNA testing [19]. Moreover, the rate of detection of polyps with high-grade dysplasia is 46.2% with FIT testing verses 69.2% with stool DNA testing, whereas the detection rate of serrated sessile polyps measuring > 1 cm is only 5.1% (FIT) versus 42.4% with stool DNA sampling [19]. These findings highlight the limits of current diagnostic screening and difficulty in establishing appropriate surrogate markers for early disease detection. Current non-invasive screening stools are not sensitive to detect pre-cancerous lesions and may miss significant early CRC. A low threshold must therefore be maintained for more invasive colonoscopy in these patients and further tools are required to support identifying early CRC. 

    Secondly, prognostic biomarkers can be used to predict disease progression including early recurrence and mortality [10][45]. KRAS is part of the RAS proto-oncogene family of GTPases which acts to turn off cell proliferation [45]. Mutations in KRAS are associated with increased risk recurrent metastatic CRC following curative resection as well as worse overall survival following hepatic metastasectomy in metastatic CRC [46][47]. Furthermore, the BRAF proto-oncogene works via the RAS-RAF-MEK-ERK pathway regulating cell transcription [48]. The BRAF V600E mutation is associated with reduced survival, including progression-free and up to 50% worse overall survival compared to BRAF wildtype [49][50][51][52]. In the emerging field of radiogenomics, a combination of radiological and genetic features may give greater prognostic sensitivity than either of these modalities in isolation [53][54]. Finally, the carcinoembryonic antigen (CEA), a high molecular weight glycoprotein is used as a biomarker to predict early recurrence in post-operative patients despite low sensitivity and specificity [55][56]. Thus, using prognostic markers may alter thresholds for further investigation of recurrent disease and provide opportunities for early intervention. Moreover, they may alter thresholds at which patients are offered more aggressive treatment.

    Additionally, predictive biomarkers are used to individually tailor treatments according to molecular subtype. KRAS mutations are associated poor response to anti-EGFR receptor therapy including cetuximab and panitummumab [57][58]. There was a 16% increase in overall response rate in KRAS wildtype patients with FOLFIRI and cetuximab compared to 4% decrease in KRAS mutants. Since KRAS mutantions are present in up to 40% of patients, a significant portion of patients can be spared expensive anti-EGFR treatment. Furthermore, irinotecan, a topoisomerase inhibitor used as part of FOLFIRI regimen, is metabolized by diphosphate-glucuronosyltransferase 1A (UGT1A). Homozygosity for UGT1A1*28 allele is associated with dose dependent increase in toxicity compared to UGT1A1*1 genotype [59]. Moreover, dihydropyrimidine dehydrogenase (DPD) is responsible for metabolizing more than 80% of 5-FU [56]. DYPD*2A and DPYD*13 variants lead to increased toxicity with evidence that reducing 5-FU dose by 25–50% can lead to a reduction in toxicity [60]. These interventions may thus lead to improved treatment response and reduced toxicity arising from ineffectual interventions. They can also help in making dose adjustments to gain maximum benefit from a selected regimen. The need to develop further biomarkers is amplified by the fact that only KRAS, NRAS, BRAF and MSI status is recommended by national guidelines in evaluating treatment response and predicting outcomes in CRC [61]. However, several potential categories of biomarkers remain under investigation.

    3. The Role of PVT1 in the Diagnosis, Treatment and Prognosis of Colorectal Cancer

     Plasmacytoma variant translocation 1 (PVT1) is a lncRNA located on human chromosome 8q24.21 adjacent to the oncogene C-MYC and undergoing p53 dependent transcription [62]. It consists of 1957 base pairs encoding between nine and 12 exons that are variably spliced along with introns giving rise to six miRNAs: miR-1204, miR-1205, miR-1206, miR-1207-3p, and miR-1207-5p [63]. Moreover, at least 14 alternately spliced transcripts have been identified at tissue-detectable levels with 11 transcripts present in normal gastrointestinal mucosa as well as adenocarcinoma . The PVT1 gene is differentially expressed among populations [64]. Furthermore, quantification of PVT1 expression pattern reveals variations between tissue types with maximal expression in ovaries, lymph nodes and bone marrow and moderate levels of expression in the colon [65]. Of note, the PVT1-217 transcript is the most abundant in the gastrointestinal tract mucosa. Furthermore, PVT1 expression is elevated in multiple cancer types including lung [66], prostate [67], cervical [68], and colon [69]. Possible functional roles for PVT1 are mediated by miRNAs, and competing endogenous RNA (ceRNA), involving regulation of gene activity through C-MYC activation [70]. There is evidence of PVT1 acting as a tumour-suppressor DNA boundary element through competition with the C-MYC promoter for shared enhancers within the gene locus [71]. Moreover, PVT1 activity may affect cell growth, replication and proliferation which may drive both carcinogenesis and chemoresistance [72].    

    Several studies have shown a potential oncogenic role for PVT1 [73] with implications for tumor initiation, progression, spread and survival. Takahashi et al. examined cell lines from 164 CRC patients, showing an increase in PVT1 expression in tumor cells which correlated with poor overall survival. Moreover, knockdown of PVT1 with siRNA promoted apoptosis and reduced the invasive capability of cells [74]. High expression of specific splice variants like PVT1 -214 is associated with poor overall survival and acquisition of stem-cell like properties including invasion and cell migration [75]. Furthermore, downstream targets of PVT1 such as miR-26b could provide both a mechanism as well as more specific biomarker readouts of PVT1 activity in CRC [65]. Poor overall survival with elevated PVT1 expression as well as increased cell proliferation, invasion and metastasis has been shown in further studies [76]. In addition, high relative levels of PVT1 in extracellular vesicles from CRC cell lines SW480 and SW620 with higher levels in the more aggressive SW620 line [77]. This was associated with co-amplification of C-MYC and C-MYC dependent genes FUBP1, EZH2, and NPM1. Moreover, this effect was reversed with inhibitory siRNA resulting in an increase in apoptosis and reduction in cell proliferation. Finally, quantification of PVT1 expression from tumors and adjacent normal tissue in 210 CRC patients showed a 51.4% increase correlating with tumor differentiation, invasion, higher stage, and lymph node spread [78]. High PVT1 expression in these patients was associated with reduced overall and disease-free survival. Interestingly, not all CRC cell lines show invasive behavior attributable to PVT1. The HCT116 CRC cell line did not show greater invasiveness compared to control lines [79]. Overall, the correlation of high PVT1 expression and reduced overall survival in CRC as well as other types of cancer has been encapsulated in a meta-analysis of 39 studies [80]. Another promising area is the identification of PVT1 polymorphisms which predict outcomes in CRC. The rs1252200336 polymorphism showed a 2.71 times higher risk of CRC in the ID vs II genotypes with lower survival in the Han Chinese population [81]. Thus, PVT1 has the potential to be a prognostic biomarker in CRC that correlates with disease severity and aggressive phenotypes. Much of the work however has been done in cell-based assays which will need to be replicated in clinical settings. Table 1 summarises the current literature explaining the oncogenic role of PVT1 through its actions on miRNAs in promoting CRC.

    PVT1 expression can be used as a readout of therapeutic drug response as well as drug resistance. In a comparison of cisplatin sensitive versus resistant CRC patients, overexpression of PVT1 was associated with cisplatin resistance [82][83]. This was mediated by upregulation of multi-drug resistance protein 1 (MRP1) and inhibition of the intrinsic apoptotic pathway with decrease in BCL-2 expression. These changes could be reversed by siRNA targeting PVT1. Furthermore, the HCT116 CRC cell line resistant to 5-FU displays high levels of PVT1 expression and upregulation of MRP1 . siRNA against PVT1 led to reduced cell survival and increased apoptosis as well as reduced MRP1 expression . Similar findings have been demonstrated within in vitro models showing 5-FU resistance with high PVT1 expression in gastric cancer [84][85] and glioma . Therefore, PVT1 expression can be used as a biomarker to rationalize treatment selection in CRC patients by predicting drug resistance. Moreover, PVT1 may itself be a target for therapeutic intervention .

    Finally, PVT1 has the potential to be a diagnostic biomarker although few studies have investigated this potential. Gharib et al. investigated PVT1 expression as a biomarker of lymph node metastasis but noted a higher AUC when combined as part of panel of biomarkers including PVT1, HOTTIP and UCA1 expression [86]. Currently, no studies have investigated the potential for PVT1 expression as a biomarker for earlier stages of CRC. This in part is limited by lack of data on temporal variation with disease progress particularly within in vivo models.

    Table 1. Summary of evidence for the role of PVT1 and miRNAs in promoting colorectal cancer.

    miRNA

    Role of PVT1

    Proposed pathogenesis pathway

    Reference

    miRNA-146a

    Decreases levels of miRNA-146a. rs13281615 G > A polymorphism on PVT1 and rs2910164 C > G polymorphism on miR‐146a leads to favourable prognosis in CRC

    PVT1/miRNA146a/COX2

    [87]

    miRNA-128

    PVT1-214 upregulates Lin28 by competing for miRNA 128. let-7 is downregulated

    PVT1-214/Lin28/let-7 axis

    [74]

    miRNA-216a-5p

    PVT1 downregulates miRNA-216a-5p and reverses tumour suppressive effect in CRC

    PVT1/miRNA-216a-5p/YBX1 axis

    [88]

    miRNA-455

    PVT1 negatively regulates miRNA-455 and upregulates RUNX

    RUNX2/PVT1/miRNA-455 regulatory axis

    [89]

    miRNA-214-3p

    PVT1 downregulates miRNA-214-3p promoting CRC progression

    PVT1/miRNA-214-3p/Insulin Receptor Substrate 1/ PI3K/Akt

    [90]

    miRNA-455-5p

    rs1252200336 polymorphism in PVT1 with ID/DD genotype leads to worse survival in CRC affecting Han Chinese population

    PVT1 suppresses miRNA-455-5p and miR-455-3p

    [80]

    miRNA-30d-5p

    PVT1 suppresses miRNA-30d-5p whilst upregulating RUNX2

    PVT1/miRNA-30d-5p/RUNX2 axis

    [84]

    miRNA-26b

    PVT1 inhibits miRNA-26b in promoting proliferation and metastases in CRC

    PVT1/miRNA-26b

    [69]

    miRNA-145

    PVT1 downregulation via sponging of miRNA-145 promotes CRC metastases

    PVT1/miRNA-145 pathway

    [85]

    miRNA-16-5p

    PVT1 binds to miR-16-5p to promote cell proliferation, migration and invasion through VEGFA/VEGFR1/AKT pathway in CRC

    PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis

    [86]

     

    This entry is adapted from 10.3390/ijms21155311

    References

    1. George: A.T.; Aggarwal, S.; Dharmavaram, S.; Menon, A.; Dube, M.; Vogler, M.; Foden, P.; Field, A. Regional variations in UK colorectal cancer screening and mortality. Lancet 2020, 392, 277–278. Available online: http://www.ncbi.nlm.nih.gov/pubmed/30064645 (accessed on 30th June 2020).
    2. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34.
    3. Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, DM.; Forman, D.; Bray, F.; Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015, 136, E359–E386.
    4. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Dyba, T.; Randi, G.; Bettio, M.; Gavin, A.; Visser, O.; Bray, F. Cancer Incidence and Mortality Patterns in Europe: Estimates for 40 Countries and 25 Major Cancers in 2018. Eur. J. Cancer 2018, 103, 356–387.
    5. CRUK. Cancer Research UK. Bowel cancer statistics. 2015–2017. Cancer Research UK. Bowel cancer statistics. 2015–2017. 2017. Available online: https://www.cancerresearchuk.org/health-profession (accessed on).
    6. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 2019, 144, 1941–1953.
    7. Yang, T.; Li, X.; Montazeri, Z.; Little, J.; Farrington, S.M.; Ioannidis, J.P.A.; Dunlop, M.G.; Campbell, H.; Timofeeva, M.; Theodoratou, E. Gene-environment interactions and colorectal cancer risk: An umbrella review of systematic reviews and meta-analyses of observational studies. Int. J. Cancer 2019, 145, 2315–2329. Available online: http://www.ncbi.nlm.nih.gov/pubmed/30536881 (accessed on 30th June 2020).
    8. Hughes, L.A.E.; Simons, C.C.J.M.; van den Brandt, P.A.; van Engeland, M.; Weijenberg, M.P. Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology. Curr. Colorectal Cancer Rep. 2017, 13, 455–469.
    9. Arnold, M.; Sierra, M.S.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017, 66, 683–691. Available online: http://www.ncbi.nlm.nih.gov/pubmed/26818619 (accessed on 30th June 2020).
    10. Patel, J.N.; Fong, M.K.; Jagosky, M. Colorectal cancer biomarkers in the era of personalized medicine. J. Pers Med. 2019, 9, 1–20.
    11. Cancer Stat Facts: Colorectal. 2020. Available online: https://seer.cancer.gov/statfacts/html/colorect.html (accessed on 30th June 2020).
    12. Chong, R.C.; Ong, M.W.; Tan, K.Y. Managing elderly with colorectal cancer. J. Gastrointest. Oncol. 2019, 10, 1266–1273. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31949947.
    13. Malvezzi, M.; Bertuccio, P.; Levi, F.; La Vecchia, C.; Negri, E. European cancer mortality predictions for the year 2011. Ann. Oncol. 2011, 22, 947–956. Available online: http://www.ncbi.nlm.nih.gov/pubmed/24759568.
    14. McGeoch, L.; Saunders, C.L.; Griffin, S.J.; Emery, J.D.; Walter, F.M.; Thompson, D.J.; Antoniou A.C.; Usher-Smith, J.C. Risk prediction models for colorectal cancer incorporating common genetic variants: A systematic review. Cancer Epidemiol. Biomark. Prev. 2019, 28, 1580–1593.
    15. Brenner, H.; Stock, C.; Hoffmeister, M. Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: Systematic review and meta-analysis of randomised controlled trials and observational studies. BMJ 2014, 9, 348.
    16. Hardcastle, J.D.; Chamberlain, J.O.; Robinson, M.H.E.; Moss, S.M.; Amar, S.S.; Balfour, T.W.; James, P.D.; Mangham C.M. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996, 348, 1472–1477.
    17. Lindholm, E.; Brevinge, H.; Haglind, E. Survival benefit in a randomized clinical trial of faecal occult blood screening for colorectal cancer. Br. J. Surg. 2008, 95, 1029–1036.
    18. Hewitson, P.; Glasziou, P.; Watson, E.; Towler, B.; Irwig, L. Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (Hemoccult): An update. Am. J. Gastroenterol. 2008, 103, 1541–1549. Available online: http://www.ncbi.nlm.nih.gov/pubmed/18479499 (accessed on 30th June 2020).
    19. Imperiale, T.F.; Ransohoff, D.F.; Itzkowitz, S.H.; Levin, T.R.; Lavin, P.; Lidgard, G.P.; Ahlquist D.A.; Berger B.M. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 2014, 370, 1287–1297. Available online: http://www.ncbi.nlm.nih.gov/pubmed/24645800 (accessed on 30th June 2020).
    20. Okada, T.; Tanaka, K.; Kawachi, H.; Ito, T.; Nishikage, T.; Odagaki, T.; Zárate, A.J.; Kronberg, U.; Lõpez-Köstner, F.; Karelovic, S.; et al. International collaboration between Japan and Chile to improve detection rates in colorectal cancer screening. Cancer 2016, 122, 71–77. Available online: https://pubmed.ncbi.nlm.nih.gov/26445309/ (accessed on 30th June 2020).
    21. Schreuders, E.H.; Ruco, A.; Rabeneck, L.; Schoen, R.E.; Sung, J.J.Y.; Young, G.P.; Kuipers, E.J. Colorectal cancer screening: A global overview of existing programmes. Gut 2015, 64, 1637–1649. Available online: http://www.ncbi.nlm.nih.gov/pubmed/26041752 (accessed on 30th June 2020).
    22. Maida, M.; Macaluso, F.S.; Ianiro, G.; Mangiola, F.; Sinagra, E.; Hold, G.; Maida, C.; Cammarota, G.; Gasbarrini, A.; Scarpulla, G. Screening of colorectal cancer: Present and future. Expert Rev. Anticancer Ther. 2017, 17, 1131–1146. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29022408 (accessed on).
    23. Akagi, T.; Inomata, M. Essential Updates 2018/2019: Essential advances in surgical and adjuvant therapies for colorectal cancer. Ann. Gastroenterol. Surg. 2020, 4, 39–46. Available online: http://www.ncbi.nlm.nih.gov/pubmed/32021957 (accessed on 30th June 2020).
    24. Keller, D.S.; Berho, M.; Perez, R.O.; Wexner, S.D.; Chand, M. The multidisciplinary management of rectal cancer. Nature Reviews Gastroenterology and Hepatology. Nat. Res. 2020. Available online: http://www.ncbi.nlm.nih.gov/pubmed/32203400 (accessed on 30th June 2020).
    25. Xie, Y.H.; Chen, Y.X.; Fang, J.Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther. 2020, 5, 22. Available online: http://www.ncbi.nlm.nih.gov/pubmed/32219002 (accessed on 30th June 2020).
    26. Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database of Systematic Reviews. 2008(3).
    27. Bender, U.; Rho, Y.S.; Barrera, I.; Aghajanyan, S.; Acoba, J.; Kavan, P. Adjuvant therapy for stages ii and iii colon cancer: Risk stratification, treatment duration, and future directions. Curr. Oncol. 2019, 26, S43–S52.
    28. Benson, A.B.; Schrag, D.; Somerfield, M.R.; Cohen, A.M.; Figueredo, A.T.; Flynn, P.J.; Krzyzanowska, M.K.; Maroun, J.; McAllister P.; Van Cutsem, E.; et al. American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer. J. Clin. Oncol. 2004, 22, 3408–3419. Available online: http://ascopubs.org/doi/10.1200/JCO.2004.05.063 (accessed on 30th June 2020).
    29. Venook, A.P.; Niedzwiecki, D.; Lenz, H.J.; Innocenti, F.; Fruth, B.; Meyerhardt, J.A.; Schrag, D.; Greene, C.; O’Neil, B.H.; Atkins, J.N; et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial. JAMA J. Am. Med. Assoc. 2017, 317, 2392–2401. Available online: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2017.7105 (accessed on 30th June 2020).
    30. Patel, J.N. Application of genotype-guided cancer therapy in solid tumors. Pharmacogenomics 2014, 15, 79–93. Available online: http://www.ncbi.nlm.nih.gov/pubmed/24329193 (accessed on 30th June 2020).
    31. Gill, S.; Loprinzi, C.L.; Sargent, D.J.; Thomé, S.D.; Alberts, S.R.; Haller, D.G.; Benedetti, J.; Francini, G.; Shepherd, L.; Seitz, J.F.; et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J. Clin. Oncol. 2004, 22, 1797–1806.
    32. Zaanan, A.; Taieb, J. Predictive and prognostic value of MSI phenotype in adjuvant colon cancer: Who and how to treat? Bulletin du Cancer 2019, 106, 129–136.
    33. Zaanan, A.; Cuilliere-Dartigues, P.; Guilloux, A.; Parc, Y.; Louvet, C.; de Gramont, A.; Tiret E., Dumont, S.; Gayet, B.; Validire, P.; et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin - ScienceDirect. Ann. Oncol. 2010, 772–780. Available online: https://www.sciencedirect.com/science/article/pii/S0923753419389367 (accessed on 30th June 2020).
    34. Bertagnolli, M.M.; Niedzwiecki, D.; Compton, C.C.; Hahn, H.P.; Hall, M.; Damas, B.; Jewell, S.D.; Mayer, R.J.; Goldberg, R.M.; Saltz, L.B.; et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and leukemia group B protocol 89803. J. Clin. Oncol. 2009, 10, 1814–1821.
    35. Reimers, M.S.; Zeestraten, E.C.M.; Kuppen, P.J.K.; Liefers, G.J.; van de Velde, C.J.H. Biomarkers in precision therapy in colorectal cancer. Gastroenterol. Rep. 2013, 1, 166–183.
    36. Chen, S.L.; Bilchik, A.J. More extensive nodal dissection improves survival for stages I to III of colon cancer: A population-based study. Ann Surg. 2006, 244, 602–610. Available online: http://www.ncbi.nlm.nih.gov/pubmed/16998369 (accessed on 30th June 2020).
    37. Davies, M.; Arumugam, P.J.; Shah, V.I.; Watkins, A.; Morgan, A.R.; Carr, N.D.; Beynon, J. The clinical significance of lymph node micrometastasis in stage I and stage II colorectal cancer. Clin. Transl. Oncol. 2008, 10, 175–179.
    38. Hurwitz, H.I.; Yi, J.; Ince, W.; Novotny, W.F.; Rosen, O. The Clinical Benefit of Bevacizumab in Metastatic Colorectal Cancer Is Independent of K‐ ras Mutation Status: Analysis of a Phase III Study of Bevacizumab with Chemotherapy in Previously Untreated Metastatic Colorectal Cancer. Oncologist 2009, 14, 22–28.
    39. Lièvre, A.; Bachet, J.B.; Le Corre, D.; Boige, V.; Landi, B.; Emile, J.F.; Côté, J.F.; Tomasic, G.; Penna, C.; Ducreux, M.; et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006, 66, 3992–3995. Available online: www.aacrjournals.org (accessed on 30th June 2020).
    40. Overman, M.J.; Lonardi, S.; Wong, K.Y.M.; Lenz, H.J.; Gelsomino, F.; Aglietta, M.; Morse, M.A.; Van Cutsem, E.; McDermott, R.; Hill, A.; et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 2018, 36, 773–779.
    41. Wong, A.L.A.; Lim, J.S.J.; Sinha, A.; Gopinathan, A.; Lim, R.; Tan, C.S.; Soh T; Venkatesh, S.; Titin, C.; Sapari, S.S.; et al. Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib. J. Transl. Med. 2015, 13, 1–9.
    42. Adenis, A.; de la Fouchardiere, C.; Paule, B.; Burtin, P.; Tougeron, D.; Wallet, J.; Dourthe, L.M.; Etienne, P.L.; Mineur, L.; Clisant, S.; et al. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: Results from a multicenter study (REBACCA) nested within a compassionate use program. BMC Cancer 2016, 16, 1–8.
    43. Museum, N. Proceedings of the china–united kingdom cancer (cukc) conference 2015 17-18. Anticancer Res. 2016, 36, 1093–1338.
    44. Pellino, G.; Gallo, G.; Pallante, P.; Capasso, R.; De Stefano, A.; Maretto, I.; Malapelle, U.; Qiu, S.; Nikolaou, S.; Barina, A.; et al. Noninvasive biomarkers of colorectal cancer: Role in diagnosis and personalised treatment perspectives. Gastroenterol. Res. Pract. 2018, 2018.
    45. Tsuchida, N.; Murugan, A.K.; Grieco, M. Kirsten Ras* oncogene: Significance of its discovery in human cancer research. Oncotarget 2016, 7, 46717–46733. Available online: http://www.ncbi.nlm.nih.gov/pubmed/27102293 (accessed on 30th June 2020).
    46. Margonis, G.A.; Spolverato, G.; Kim, Y.; Karagkounis, G.; Choti, M.A.; Pawlik, T.M. Effect of KRAS Mutation on Long-Term Outcomes of Patients Undergoing Hepatic Resection for Colorectal Liver Metastases. Ann Surg Oncol. 2015, 22, 4158–4165.
    47. Tie, J.; Lipton, L.; Desai, J.; Gibbs, P.; Jorissen, R.N.; Christie, M.; Drummond, K.J.; Thomson, B.N.J.; Usatoff, V.; Evans, P.M.; et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin. Cancer Res. 2011, 17, 1122–1130. Available online: http://www.ncbi.nlm.nih.gov/pubmed/21239505 (accessed on 30th June 2020).
    48. Guo, X.; Xu, Y.; Zhao, Z. In-depth genomic data analyses revealed complex transcriptional and epigenetic dysregulations of BRAFV600E in melanoma. Mol. Cancer 2015, 14, 60.
    49. Venderbosch, S.; Nagtegaal, I.D.; Maughan, T.S.; Smith, C.G.; Cheadle, J.P.; Fisher, D.; Kaplan, R.; Quirke, P.; Seymour, M.T.; Richman, S.D.; et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014, 20, 5322–5330. Available online: http://www.ncbi.nlm.nih.gov/pubmed/25139339 (accessed on 30th June 2020).
    50. Yokota, T. Are KRAS/BRAF Mutations Potent Prognostic and/or Predictive Biomarkers in Colorectal Cancers? Anticancer Agents Med. Chem. 2012, 12, 163–171.
    51. Yokota, T.; Ura, T.; Shibata, N.; Takahari, D.; Shitara, K.; Nomura, M.; Kondo, C.; Mizota, A.; Utsunomiya, S.; Muro, K.; et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br. J. Cancer 2011, 104, 856–862.
    52. Van Cutsem, E.; Köhne, C.H.; Láng, I.; Folprecht, G.; Nowacki, M.P.; Cascinu, S.; Shchepotin, I.; Maurel, J.; Cunningham, D.; Tejpar, S.; et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol. 2011, 29, 2011–2019.
    53. Badic, B.; Hatt, M.; Durand, S.; Jossic-Corcos CLe Simon, B.; Visvikis, D.; Corcos, L. Radiogenomics-based cancer prognosis in colorectal cancer. Sci. Rep. 2019, 9, 1–7.
    54. Horvat, N.; Veeraraghavan, H.; Pelossof, R.A.; Fernandes, M.C.; Arora, A.; Khan, M.; Marco, M.; Cheng, C.T.; Gonen, M.; Golia Pernicka, J. S.; et al. Radiogenomics of rectal adenocarcinoma in the era of precision medicine: A pilot study of associations between qualitative and quantitative MRI imaging features and genetic mutations. Eur. J. Radiol. 2019, 113, 174–181.
    55. Chao, M.; Gibbs, P. Caution is required before recommending routine carcinoembryonic antigen and imaging follow-up for patients with early-stage colon cancer. J. Clin. Oncol. 2009, 27, e279–e280. Available online: http://www.ncbi.nlm.nih.gov/pubmed/19901127 (accessed on 30th June 2020).
    56. Koulis, C.; Yap, R.; Engel, R.; Jardé, T.; Wilkins, S.; Solon, G.; Shapiro, J.D.; Abud, H.; McMurrick, P. Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer. Cancers (Basel) 2020, 12, 812. Available online: http://www.ncbi.nlm.nih.gov/pubmed/32231042 (accessed on 30th June 2020).
    57. Karapetis, C.S.; Khambata-Ford, S.; Jonker, D.J.; O’Callaghan, C.J.; Tu, D.; Tebbutt, N.C.; Simes, J.R.; Chalchal, H.; Shapiro, J.D.; Robitaille, S.; et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359, 1757–1765.
    58. Amado, R.G.; Wolf, M.; Peeters, M.; Van Cutsem, E.; Siena, S.; Freeman, D.J.; Juan, T.; Sikorski, R.; Suggs, S.; Radinsky, R.; et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 2008, 26, 1626–1634. Available online: http://www.ncbi.nlm.nih.gov/pubmed/18316791 (accessed on 30th June 2020).
    59. Palomaki, G.E.; Bradley, L.A.; Douglas, M.P.; Kolor, K.; Dotson, W.D. Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet. Med. 2009, 11, 21–34. Available online: http://www.ncbi.nlm.nih.gov/pubmed/19125129 (accessed on 30th June 2020).
    60. Amstutz, U.; Henricks, L.M.; Offer, S.M.; Barbarino, J.; Schellens, J.H.M.; Swen, J.J.; Klein, T.E.; McLeod, H.L.; Caudle, K.E.; Diasio, R.B.; et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin. Pharmacol. Ther. 2018, 103, 210–216.
    61. Shinagawa, T.; Tanaka, T.; Nozawa, H.; Emoto, S.; Murono, K.; Kaneko, M.; Sasaki, K.; Otani, K.; Nishikawa, T.; Hata, K.; et al. Comparison of the guidelines for colorectal cancer in Japan, the USA and Europe. Ann. Gastroenterol. Surg. 2018, 2, 6–12. Available online: /pmc/articles/PMC5881304/?report=abstract (accessed on 30th June 2020).
    62. Jin, K.; Wang, S.; Zhang, Y.; Xia, M.; Mo, Y.; Li, X.; Li, G.; Zeng, Z.; Xiong, W.; He, Y. Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis. Cell. Mol. Life Sci. 2019, 76, 4275–4289. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31309249 (accessed on 30th June 2020).
    63. Ilboudo, A.; Chouhan, J.; McNeil, B.K.; Osborne, J.R.; Ogunwobi, O.O. PVT1 Exon 9: A Potential Biomarker of Aggressive Prostate Cancer? Int. J. Environ. Res. Public Health 2015, 13, ijerph13010012. Available online: http://www.ncbi.nlm.nih.gov/pubmed/26703666 (accessed on 30th June 2020).
    64. Pan, X.; Zheng, G.; Gao, C. LncRNA PVT1: A Novel Therapeutic Target for Cancers. Clin. Lab. 2018, 64, 655–662. Available online: http://www.clin-lab-publications.com/article/2724 (accessed on 30th June 2020).
    65. Pal, G.; Ogunwobi, O.O. Copy number-based quantification assay for non-invasive detection of PVT1-derived transcripts. PLoS ONE 2019, 14, e0226620. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31877167 (accessed on 30th June 2020).
    66. Li, H.; Chen, S.; Liu, J.; Guo, X.; Xiang, X.; Dong, T.; Ran, P.; Li, Q.; Zhu, B.; Xhang, X.; et al. Long non-coding RNA PVT1-5 promotes cell proliferation by regulating miR-126/SLC7A5 axis in lung cancer. Biochem. Biophys. Res. Commun. 2018, 495, 2350–2355.
    67. Pal, G.; Huaman, J.; Levine, F.; Orunmuyi, A.; Oluwabunmi Olapade-Olaopa, E.; Onagoruwa, O.T.; Ogunwobi, O.O. Long noncoding RNA from PVT1 exon 9 is overexpressed in prostate cancer and induces malignant transformation and castration resistance in prostate epithelial cells. Genes (Basel) 2019, 10. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31766781 (accessed on 30th June 2020).
    68. Gao, Y.-L.; Zhao, Z.-S.; Zhang, M.-Y.; Han, L.-J.; Dong, Y.-J.; Xu, B. Long Noncoding RNA PVT1 Facilitates Cervical Cancer Progression via Negative Regulating of miR-424. Oncol. Res. 2017, 25, 1391–1398. Available online: http://www.ncbi.nlm.nih.gov/pubmed/28276314 (accessed on 30th June 2020).
    69. Zhang, R.; Li, J.; Yan, X.; Jin, K.; Li, W.; Liu, X.; Zhao, J.; Shang, W.; Liu, Y. Long noncoding RNA plasmacytoma variant translocation 1 (PVT1) promotes colon cancer progression via endogenous sponging miR-26b. Med. Sci. Monit. 2018, 24, 8685–8692.
    70. Cho, S.W.; Xu, J.; Sun, R.; Mumbach, M.R.; Carter, A.C.; Chen, Y.G.; Yost, K.E.; Kim, J.; He, J.; Nevins, S.A.; et al. Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element. Cell 2018, 173, 1398–1412.e22. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29731168 (accessed on 30th June 2020).
    71. Derderian, C.; Orunmuyi, A.T.; Oluwabunmi Olapade-Olaopa, E.; Ogunwobi, O.O. PVT1 signaling is a mediator of cancer progression. Front Oncol. 2019, 9, 1–8.
    72. Song, T.; Yan, L.; Cai, K.; Zhao, T.; Xu, M. Downregulation of long noncoding RNA PVT1 attenuates paclitaxel resistance in glioma cells. Cancer Biomark. 2018, 23, 447–453. Available online: http://www.ncbi.nlm.nih.gov/pubmed/30347597 (accessed on 30th June 2020).
    73. Takahashi, Y.; Sawada, G.; Kurashige, J.; Uchi, R.; Matsumura, T.; Ueo, H.; Takano, Y.; Eguchi, H.; Sudo, T.; Sugimachi, K.; et al. Amplification of PVT-1 is involved in poor prognosis via apoptosis inhibition in colorectal cancers. Br. J. Cancer 2014, 110, 164–171.
    74. He, F.; Song, Z.; Chen, H.; Chen, Z.; Yang, P.; Li, W.; Yang, Z.; Zhang, T.; Wang, F.; Wei, J.; et al. Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene 2019, 38, 164–179.
    75. Wang, C.; Zhu, X.; Pu, C.; Song, X. Upregulated plasmacytoma variant translocation 1 promotes cell proliferation, invasion and metastasis in colorectal cancer. Mol. Med. Rep. 2018, 17, 6598–6604.
    76. Guo, K.; Yao, J.; Yu, Q.; Li, Z.; Huang, H.; Cheng, J.; Wang, Z.; Zhu, Y. The expression pattern of long non-coding RNA PVT1 in tumor tissues and in extracellular vesicles of colorectal cancer correlates with cancer progression. Tumor Biol. 2017, 39, 1010428317699122. Available online: http://www.ncbi.nlm.nih.gov/pubmed/28381186 (accessed on 30th June 2020).
    77. Fan, H.; Zhu, J.-H.; Yao, X.-Q. Long non-coding RNA PVT1 as a novel potential biomarker for predicting the prognosis of colorectal cancer. Int. J. Biol. Markers 2018, 33, 1724600818777242. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29888675 (accessed on 30th June 2020).
    78. Chen, Z.; Cai, X.; Chang, L.; Xia, Y.; Wang, L.; Hou, Y.; Li, L.; Pan, D.; Li, F.; Liu, S.; et al. LINC00152 is a potential biomarker involved in the modulation of biological characteristics of residual colorectal cancer cells following chemoradiotherapy. Oncol Lett. 2018, 15, 4177–4184.
    79. Zou, B.; Wang, D.; Xu, K.; Liu, J.-L.; Yuan, D.-Y.; Meng, Z.; Zhang, B. Prognostic value of long non-coding RNA plasmacytoma variant translocation1 in human solid tumors: A meta-analysis. Medicine (Baltimore) 2019, 98, e16087. Available online: http://www.ncbi.nlm.nih.gov/pubmed/31277104 (accessed on 30th June 2020).
    80. Zhang, L.; Mao, J. Long-Chain Noncoding RNA PVT1 Gene Polymorphisms Are Associated with the Risk and Prognosis of Colorectal Cancer in the Han Chinese Population. Genet. Test Mol. Biomark. 2019, 23, 728–736. Available online: https://pubmed.ncbi.nlm.nih.gov/31509024/ (accessed on 30th June 2020).
    81. Ping, G.; Xiong, W.; Zhang, L.; Li, Y.; Zhang, Y.; Zhao, Y. Silencing long noncoding RNA PVT1 inhibits tumorigenesis and cisplatin resistance of colorectal cancer. Am. J. Transl. Res. 2018, 10, 138–149. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29423000 (accessed on 30th June 2020).
    82. Chen, D.-L.; Xu, R.-H. The emerging role of long non-coding RNAs in the drug resistance of colorectal cancer. Int. J. Clin. Exp. Pathol. 2018, 11, 4735–4743.
    83. Fan, H.; Zhu, J.H.; Yao, X.Q. Knockdown of long non-coding RNA PVT1 reverses Multidrug resistance in colorectal cancer cells. Mol. Med. Rep. 2018, 17, 8309–8315.
    84. Yu, X.; Zhao, J.; He, Y. Long non-coding RNA PVT1 functions as an oncogene in hu-man colon cancer through miR-30d-5p/RUNX2 axis. JBUON 2018, 23, 48–54.
    85. Wang, Z.; Su, M.; Xiang, B.; Zhao, K.; Qin, B. Circular RNA PVT1 promotes metastasis via miR-145 sponging in CRC. Biochem. Biophys. Res. Commun. 2019, 512, 716–722. Available online: https://pubmed.ncbi.nlm.nih.gov/30922567/ (accessed on 30th June 2020).
    86. Wu, H.; Wei, M.; Jiang, X.; Tan, J.; Xu, W.; Fan, X.; Zhang, R.; Ding, C.; Zhao, F.; Shao, X.; et al. lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis. Mol. Ther. Nucleic Acids 2020, 20, 438–450. Available online: https://pubmed.ncbi.nlm.nih.gov/32276209/ (accessed on 30th June 2020).
    87. Zhang, W.; Xiao, J.; Lu, X.; Liu, T.; Jin, X.; Xiao, Y.; He, X. PVT1 (rs13281615) and miR-146a (rs2910164) polymorphisms affect the prognosis of colon cancer by regulating COX2 expression and cell apoptosis. J. Cell Physiol. 2019, 234, 17538–17548. Available online: https://pubmed.ncbi.nlm.nih.gov/30820968/ (accessed on 30th June 2020).
    88. Zeng, X.; Liu, Y.; Zhu, H.; Chen, D.; Hu, W. Downregulation of miR-216a-5p by long noncoding RNA PVT1 suppresses colorectal cancer progression via modulation of YBX1 expression. Cancer Manag. Res. 2019, 11, 6981–6993. Available online: https://pubmed.ncbi.nlm.nih.gov/31440087/ (accessed on 30th June 2020).
    89. Chai, J.; Guo, D.; Ma, W.; Han, D.; Dong, W.; Guo, H.; Zhang, Y. A feedback loop consisting of RUNX2/LncRNA-PVT1/miR-455 is involved in the progression of colorectal cancer. Am. J. Cancer Res. 2018, 8, 538–50. Available online: http://www.ncbi.nlm.nih.gov/pubmed/29637007 (accessed on 30th June 2020).
    90. Shang, A.Q.; Wang, W.W.; Yang, Y.B.; Gu, C.Z.; Ji, P.; Chen, C.; Zeng, B.J.; Wu,, J.L.; Lu, W.Y.; Sun, Z.J.; et al. Knockdown of long noncoding RNA PVT1 suppresses cell proliferation and invasion of colorectal cancer via upregulation of microRNA-214-3p. Am. J. Physiol. Gastrointest Liver Physiol. 2019, 317, G222–G232. Available online: https://pubmed.ncbi.nlm.nih.gov/31125260/ (accessed on 30th June 2020).
    91. Yu, X.; Zhao, J.; He, Y. Long non-coding RNA PVT1 functions as an oncogene in hu-man colon cancer through miR-30d-5p/RUNX2 axis. JBUON 2018, 23, 48–54.
    92. Wang, Z.; Su, M.; Xiang, B.; Zhao, K.; Qin, B. Circular RNA PVT1 promotes metastasis via miR-145 sponging in CRC. Biochem. Biophys. Res. Commun. 2019, 512, 716–722. Available online: https://pubmed.ncbi.nlm.nih.gov/30922567/ (accessed on 30th June 2020).
    93. Wu, H.; Wei, M.; Jiang, X.; Tan, J.; Xu, W.; Fan, X.; Zhang, R.; Ding, C.; Zhao, F.; Shao, X.; et al. lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis. Mol. Ther. Nucleic Acids 2020, 20, 438–450. Available online: https://pubmed.ncbi.nlm.nih.gov/32276209/ (accessed on 30th June 2020).
    More