Role of salt‑inducible kinase 2 in the malignant behavior and glycolysis of colorectal cancer cells

Ni,Xiaohong; Feng,Yongjiang; Fu,Xiangwei

doi:10.3892/mmr.2021.12460

Role of salt‑inducible kinase 2 in the malignant behavior and glycolysis of colorectal cancer cells

Authors:
- Xiaohong Ni
- Yongjiang Feng
- Xiangwei Fu
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, Yancheng Dafeng People's Hospital, Yancheng, Jiangsu 224100, P.R. China, Department of General Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570105, P.R. China
Published online on: September 24, 2021 https://doi.org/10.3892/mmr.2021.12460
Article Number: 822
Copyright: © Ni et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Currently, surgery, chemotherapy and radiation therapy are the conventional approaches used to treat CRC. However, these therapy strategies cause several side effects. The present study aimed to develop an alternative and more effective treatment approach for patients with CRC. It has been reported that salt‑inducible kinase 2 (SIK2) acts as an oncogene. Therefore, in the present study, the expression levels of SIK2 were determined in CRC cells using western blot analysis and reverse transcription‑quantitative PCR. In addition, SIK2 was knocked down in CRC cells to evaluate its role in cell proliferation, migration, invasion and glycolysis using Cell Counting Kit‑8, wound healing, Transwell assays and glycolysis cell‑based assay kit, respectively. Additionally, the target genes of SIK2 were identified using bioinformatics analysis, while SIK2 overexpression experiments were carried out to determine whether SIK2 could regulate CRC cell malignant behavior and glycolysis. The results revealed that SIK2 was upregulated in CRC cells. Furthermore, SIK2 knockdown attenuated CRC cell proliferation, migration, invasion and glycolysis. Bioinformatics analysis predicted that SIK2 could interact with tripartite motif containing 28 (TRIM28), while TRIM28 overexpression could reverse the effects of SIK2 silencing on cell proliferation, migration, invasion and glycolysis. This finding indicated that the aforementioned effects of SIK2 were mediated by regulating TRIM28. In conclusion, the findings of the present study suggested that SIK2 may be involved in CRC carcinogenesis and glycolysis by regulating TRIM28 expression. These findings could provide a novel approach to targeted therapy and clinical diagnosis of CRC in the future.

View Figures

View References

1	Janney A, Powrie F and Mann EH: Host-microbiota maladaptation in colorectal cancer. Nature. 585:509–517. 2020. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Johdi NA and Sukor NF: Colorectal cancer immunotherapy: Options and strategies. Front Immunol. 11:16242020. View Article : Google Scholar : PubMed/NCBI
4	Schmoll HJ, Van Cutsem E, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, et al: ESMO consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 23:2479–2516. 2012. View Article : Google Scholar : PubMed/NCBI
5	Van Cutsem E, Cervantes A, Nordlinger B and Arnold D; ESMO Guidelines Working Group, : Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 25 (Suppl 3):iii1–iii9. 2014. View Article : Google Scholar : PubMed/NCBI
6	Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K, Xu RH, Kim TW, Ismail F, Tan IB, Yeh KH, et al: Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: A JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol. 29:44–70. 2018. View Article : Google Scholar : PubMed/NCBI
7	Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, et al: ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 27:1386–1422. 2016. View Article : Google Scholar : PubMed/NCBI
8	Bonjer HJ, Deijen CL, Abis GA, Cuesta MA, van der Pas MH, de Lange-de Klerk ES, Lacy AM, Bemelman WA, Andersson J, Angenete E, et al: A randomized trial of laparoscopic versus open surgery for rectal cancer. N Engl J Med. 372:1324–1332. 2015. View Article : Google Scholar : PubMed/NCBI
9	MacFarlane JK, Ryall RD and Heald RJ: Mesorectal excision for rectal cancer. Lancet. 341:457–460. 1993. View Article : Google Scholar : PubMed/NCBI
10	Park SC, Sohn DK, Kim MJ, Chang HJ, Han KS, Hyun JH, Joo J and Oh JH: Phase II clinical trial to evaluate the efficacy of transanal endoscopic total mesorectal excision for rectal cancer. Dis Colon Rectum. 61:554–560. 2018. View Article : Google Scholar : PubMed/NCBI
11	Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL and Siegel RL: Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 69:363–385. 2019. View Article : Google Scholar : PubMed/NCBI
12	Garg MB, Lincz LF, Adler K, Scorgie FE, Ackland SP and Sakoff JA: Predicting 5-fluorouracil toxicity in colorectal cancer patients from peripheral blood cell telomere length: A multivariate analysis. Br J Cancer. 107:1525–1533. 2012. View Article : Google Scholar : PubMed/NCBI
13	Ogura A, Konishi T, Cunningham C, Garcia-Aguilar J, Iversen H, Toda S, Lee IK, Lee HX, Uehara K, Lee P, et al: Neoadjuvant (chemo) radiotherapy with total mesorectal excision only is not sufficient to prevent lateral local recurrence in enlarged nodes: Results of the multicenter lateral node study of patients with low cT3/4 rectal cancer. J Clin Oncol. 37:33–43. 2019. View Article : Google Scholar : PubMed/NCBI
14	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI
15	Patel JN: Application of genotype-guided cancer therapy in solid tumors. Pharmacogenomics. 15:79–93. 2014. View Article : Google Scholar : PubMed/NCBI
16	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. 2018:23978632018.PubMed/NCBI
17	Ogunwobi OO, Mahmood F and Akingboye A: Biomarkers in colorectal cancer: Current research and future prospects. Int J Mol Sci. 21:53112020. View Article : Google Scholar : PubMed/NCBI
18	Patel JN, Fong MK and Jagosky M: Colorectal cancer biomarkers in the era of personalized medicine. J Pers Med. 9:32019. View Article : Google Scholar : PubMed/NCBI
19	Yiu AJ and Yiu CY: Biomarkers in colorectal cancer. Anticancer Res. 36:1093–1102. 2016.PubMed/NCBI
20	Zong S, Dai W, Fang W, Guo X and Wang K: SIK2 promotes cisplatin resistance induced by aerobic glycolysis in breast cancer cells through PI3K/AKT/mTOR signaling pathway. Biosci Rep. May 27–2020.(Epub ahead of Print).
21	Zhao J, Zhang X, Gao T, Wang S, Hou Y, Yuan P, Yang Y, Yang T, Xing J, Li J and Liu S: SIK2 enhances synthesis of fatty acid and cholesterol in ovarian cancer cells and tumor growth through PI3K/Akt signaling pathway. Cell Death Dis. 11:252020. View Article : Google Scholar : PubMed/NCBI
22	Sun Z, Niu S, Xu F, Zhao W, Ma R and Chen M: CircAMOTL1 promotes tumorigenesis through miR-526b/SIK2 axis in cervical cancer. Front Cell Dev Biol. 8:5681902020. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D, et al: The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 483:603–607. 2012. View Article : Google Scholar : PubMed/NCBI
25	Oughtred R, Rust J, Chang C, Breitkreutz BJ, Stark C, Willems A, Boucher L, Leung G, Kolas N, Zhang F, et al: The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions. Protein Sci. 30:187–200. 2021. View Article : Google Scholar : PubMed/NCBI
26	Li J, Xu X, Jiang Y, Hansbro NG, Hansbro PM, Xu J and Liu G: Elastin is a key factor of tumor development in colorectal cancer. BMC Cancer. 20:2172020. View Article : Google Scholar : PubMed/NCBI
27	Mauri G, Sartore-Bianchi A, Russo AG, Marsoni S, Bardelli A and Siena S: Early-onset colorectal cancer in young individuals. Mol Oncol. 13:109–131. 2019. View Article : Google Scholar : PubMed/NCBI
28	Zhang X, Zhang H, Shen B and Sun XF: Chromogranin-A expression as a novel biomarker for early diagnosis of colon cancer patients. Int J Mol Sci. 20:29192019. View Article : Google Scholar : PubMed/NCBI
29	Doll R and Peto R: The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 66:1191–1308. 1981. View Article : Google Scholar : PubMed/NCBI
30	Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, et al: Environment dominates over host genetics in shaping human gut microbiota. Nature. 555:210–215. 2018. View Article : Google Scholar : PubMed/NCBI
31	Liang Q, Chiu J, Chen Y, Huang Y, Higashimori A, Fang J, Brim H, Ashktorab H, Ng SC, Ng SSM, et al: Fecal bacteria act as novel biomarkers for noninvasive diagnosis of colorectal cancer. Clin Cancer Res. 23:2061–2070. 2017. View Article : Google Scholar : PubMed/NCBI
32	Ladabaum U, Dominitz JA, Kahi C and Schoen RE: Strategies for colorectal cancer screening. Gastroenterology. 158:418–432. 2020. View Article : Google Scholar : PubMed/NCBI
33	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
34	Cuezva JM, Ortega AD, Willers I, Sánchez-Cenizo L, Aldea M and Sánchez-Aragó M: The tumor suppressor function of mitochondria: Translation into the clinics. Biochim Biophys Acta. 1792:1145–1158. 2009. View Article : Google Scholar : PubMed/NCBI
35	Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini KR, Vokes NI, Stephanopoulos G, Cantley LC, Metallo CM and Locasale JW: Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol. 76:325–334. 2011. View Article : Google Scholar : PubMed/NCBI
36	Lunt SY and Vander Heiden MG: Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 27:441–464. 2011. View Article : Google Scholar : PubMed/NCBI
37	Enzo E, Santinon G, Pocaterra A, Aragona M, Bresolin S, Forcato M, Grifoni D, Pession A, Zanconato F, Guzzo G, et al: Aerobic glycolysis tunes YAP/TAZ transcriptional activity. EMBO J. 34:1349–1370. 2015. View Article : Google Scholar : PubMed/NCBI
38	Samec M, Liskova A, Koklesova L, Samuel SM, Zhai K, Buhrmann C, Varghese E, Abotaleb M, Qaradakhi T, Zulli A, et al: Flavonoids against the warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism. EPMA J. 11:377–398. 2020. View Article : Google Scholar : PubMed/NCBI
39	Gao T, Zhang X, Zhao J, Zhou F, Wang Y, Zhao Z, Xing J, Chen B, Li J and Liu S: SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer. Cancer Letters. 469:89–101. 2020. View Article : Google Scholar : PubMed/NCBI
40	Lin LF, Li CF, Wang WJ, Yang WM, Wang DD, Chang WC, Lee WH and Wang JM: Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer. PLoS One. 8:e730332013. View Article : Google Scholar : PubMed/NCBI
41	Yokoe T, Toiyama Y, Okugawa Y, Tanaka K, Ohi M, Inoue Y, Mohri Y, Miki C and Kusunoki M: KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Ann Surg Oncol. 17:821–828. 2010. View Article : Google Scholar : PubMed/NCBI
42	Wang YY, Li L, Zhao ZS and Wang HJ: Clinical utility of measuring expression levels of KAP1, TIMP1 and STC2 in peripheral blood of patients with gastric cancer. World J Surg Oncol. 11:812013. View Article : Google Scholar : PubMed/NCBI
43	Qi ZX, Cai JJ, Chen LC, Yue Q, Gong Y, Yao Y and Mao Y: TRIM28 as an independent prognostic marker plays critical roles in glioma progression. J Neurooncol. 126:19–26. 2016. View Article : Google Scholar : PubMed/NCBI
44	Fitzgerald S, Sheehan KM, O'Grady A, Kenny D, O'Kennedy R, Kay EW and Kijanka GS: Relationship between epithelial and stromal TRIM28 expression predicts survival in colorectal cancer patients. J Gastroenterol Hepatol. 28:967–974. 2013. View Article : Google Scholar : PubMed/NCBI
45	Fitzgerald S, Espina V, Liotta L, Sheehan KM, O'Grady A, Cummins R, O'Kennedy R, Kay EW and Kijanka GS: Stromal TRIM28-associated signaling pathway modulation within the colorectal cancer microenvironment. J Transl Med. 16:892018. View Article : Google Scholar : PubMed/NCBI