Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression Corrigendum in /10.3892/ijo.2023.5591

Zhao,Shuang; Wu,Lisha; Kuang,Yehong; Su,Juan; Luo,Zhongling; Wang,Yan; Li,Jinmao; Zhang,Jianglin; Chen,Wangqing; Li,Fangfang; He,Yijing; Tao,Juan; Zhou,Jianda; Xu,Xiaowei; Peng,Cong; Chen,Xiang

doi:10.3892/ijo.2018.4579

Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression

Corrigendum in: /10.3892/ijo.2023.5591

Authors:
- Shuang Zhao
- Lisha Wu
- Yehong Kuang
- Juan Su
- Zhongling Luo
- Yan Wang
- Jinmao Li
- Jianglin Zhang
- Wangqing Chen
- Fangfang Li
- Yijing He
- Juan Tao
- Jianda Zhou
- Xiaowei Xu
- Cong Peng
- Xiang Chen
View Affiliations

Affiliations: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Plastic Surgery of The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Published online on: October 1, 2018 https://doi.org/10.3892/ijo.2018.4579
Pages: 2397-2408
Copyright: © Zhao 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

Cluster of differentiation (CD)147, as a transmembrane glycoprotein, is highly expressed in a variety of tumors. Accumulating evidence has demonstrated that CD147 serves critical roles in tumor cell death and survival; however, the underlying mechanism requires further investigation. In the present study, it was revealed that CD147 knockdown significantly increased melanoma cell apoptosis. In addition, downregulation of CD147 reversed the malignant phenotype of melanoma, as demonstrated by the induction of tumor cell apoptosis in a xenograft mouse model. In addition, a human apoptosis antibody array was performed and 9 differentially expressed apoptosis-related proteins associated with CD147 were identified, including insulin-like growth factor-binding protein 2 (IGFBP2). Additionally, CD147 knockdown was observed to significantly decreased IGFBP2 expression at the mRNA and protein levels in melanoma cells. Providing that IGFBP2 is a downstream molecule in the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, the effects of CD147 on this particular pathway were investigated. Interestingly, the expression of phosphorylated (p)-AKT and p‑mechanistic target of rapamycin was attenuated, whereas PTEN was markedly upregulated in CD147-underexpressing melanoma cells. Furthermore, application of a PI3K‑specific inhibitor also decreased IGFBP2 expression. Importantly, IGFBP2 was highly expressed in clinical tissues of melanoma compared with the control group, and its expression exhibited a positive association with CD147. The present study revealed that CD147 served a critical role in mediating the apoptosis of melanoma cells via IGFBP2 and the PTEN/PI3K/AKT signaling pathway. IGFBP2 and CD147 were observed to be overexpressed in clinical melanoma tissues; IGFBP2 was shown to be positively associated with CD147 expression, suggesting that CD147 may be considered as a potential therapeutic target for chemotherapy or prevention for in melanoma.

View Figures

View References

1	Zimmer L, Haydu LE, Menzies AM, Scolyer RA, Kefford RF, Thompson JF, Schadendorf D and Long GV: Incidence of new primary melanomas after diagnosis of stage III and IV melanoma. J Clin Oncol. 32:816–823. 2014. View Article : Google Scholar
2	Arnold M, Holterhues C, Hollestein LM, Coebergh JW, Nijsten T, Pukkala E, Holleczek B, Tryggvadóttir L, Comber H, Bento MJ, et al: Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatol Venereol. 28:1170–1178. 2014. View Article : Google Scholar
3	Yin H, Shao Y and Chen X: The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma. Neurol Sci. 38:129–136. 2017. View Article : Google Scholar
4	Kuang YH, Chen X, Su J, Wu LS, Liao LQ, Li D, Chen ZS and Kanekura T: RNA interference targeting the CD147 induces apoptosis of multi-drug resistant cancer cells related to XIAP depletion. Cancer Lett. 276:189–195. 2009. View Article : Google Scholar
5	Xie W, Xie H, Liu F, Li W, Dan J, Mei Y, Dan L, Xiao X, Li J and Chen X: Propranolol induces apoptosis of human umbilical vein endothelial cells through downregulation of CD147. Br J Dermatol. 168:739–748. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zhao S, Kuang YH and Chen X: Overexpression of CD147 inhibits Chinese Hamster Ovary cells apoptosis due to inducing methotrexate efflux. J Dermatol. 39:170. 2012.
7	Yu JS and Cui W: Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 143:3050–3060. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lian C, Guo Y, Zhang J, Chen X and Peng C: Targeting CD147 is a Novel Strategy for Antitumor Therapy. Curr Pharm Des. 23:4410–4421. 2017. View Article : Google Scholar : PubMed/NCBI
9	Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA and Hafen E: Living with lethal PIP3 levels: Viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science. 295:2088–2091. 2002. View Article : Google Scholar : PubMed/NCBI
10	Abraham J: PI3K/AKT/mTOR pathway inhibitors: The ideal combination partners for breast cancer therapies? Expert Rev Anticancer Ther. 15:51–68. 2015. View Article : Google Scholar
11	Bucheit AD, Chen G, Siroy A, Tetzlaff M, Broaddus R, Milton D, Fox P, Bassett R, Hwu P, Gershenwald JE, et al: Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations. Clin Cancer Res. 20:5527–5536. 2014. View Article : Google Scholar : PubMed/NCBI
12	Dong Y, Richards JA, Gupta R, Aung PP, Emley A, Kluger Y, Dogra SK, Mahalingam M and Wajapeyee N: PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene. 33:4632–4642. 2014. View Article : Google Scholar
13	Zhang W and Fuller G: IGFBP2 as a brain tumor oncogene. Cancer Biol Ther. 6:995–996. 2007.PubMed/NCBI
14	Sztefko K, Hodorowicz-Zaniewska D, Popiela T and Richter P: IGF-I, IGF-II, IGFBP2, IGFBP3 and acid-labile subunit (ALS) in colorectal cancer patients before surgery and during one year follow up in relation to age. Adv Med Sci. 54:51–58. 2009. View Article : Google Scholar : PubMed/NCBI
15	Moore LM, Holmes KM, Smith SM, Wu Y, Tchougounova E, Uhrbom L, Sawaya R, Bruner JM, Fuller GN and Zhang W: IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas. Proc Natl Acad Sci USA. 106:16675–16679. 2009. View Article : Google Scholar : PubMed/NCBI
16	Zeng W, Su J, Wu L, Yang D, Long T, Li D, Kuang Y, Li J, Qi M, Zhang J, et al: CD147 promotes melanoma progression through hypoxia-induced MMP2 activation. Curr Mol Med. 14:163–173. 2014. View Article : Google Scholar
17	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
18	Chen X, Lin J, Kanekura T, Su J, Lin W, Xie H, Wu Y, Li J, Chen M and Chang J: A small interfering CD147-targeting RNA inhibited the proliferation, invasiveness, and metastatic activity of malignant melanoma. Cancer Res. 66:11323–11330. 2006. View Article : Google Scholar : PubMed/NCBI
19	Council NR: Guide for the Care and Use of Laboratory Animals. The National Academies Press; Washington, DC: 1996
20	Su J, Gao T, Jiang M, Wu L, Zeng W, Zhao S, Peng C and Chen X: CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma. Oncotarget. 7:64778–64784. 2016. View Article : Google Scholar : PubMed/NCBI
21	Gou X, Tang X, Kong DK, He X, Gao X, Guo N, Hu Z, Zhao Z and Chen Y: CD147 is increased in HCC cells under starvation and reduces cell death through upregulating p-mTOR in vitro. Apoptosis. 21:110–119. 2016. View Article : Google Scholar
22	Li QQ, Wang WJ, Xu JD, Cao XX, Chen Q, Yang JM and Xu ZD: Up-regulation of CD147 and matrix metalloproteinase-2, -9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci. 98:1767–1774. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zou W, Yang H, Hou X, Zhang W, Chen B and Xin X: Inhibition of CD147 gene expression via RNA interference reduces tumor cell invasion, tumorigenicity and increases chemosensitivity to paclitaxel in HO-8910 pm cells. Cancer Lett. 248:211–218. 2007. View Article : Google Scholar
24	Chen H, Fok KL, Jiang X, Jiang J, Chen Z, Gui Y, Chan HC and Cai Z: CD147 regulates apoptosis in mouse spermatocytes but not spermatogonia. Hum Reprod. 27:1568–1576. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wang C, Fok KL, Cai Z, Chen H and Chan HC: CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways. Oncotarget. 8:3132–3143. 2017.
26	Tang J, Guo YS, Zhang Y, Yu XL, Li L, Huang W, Li Y, Chen B, Jiang JL and Chen ZN: CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma. Cell Death Differ. 19:1779–1790. 2012. View Article : Google Scholar : PubMed/NCBI
27	Reynolds CM, Perry JK and Vickers MH: Manipulation of the growth hormone-insulin-like growth factor (GH-IGF) axis: A treatment strategy to reverse the effects of early life developmental programming. Int J Mol Sci. 18:182017. View Article : Google Scholar
28	Podlutsky A, Valcarcel-Ares MN, Yancey K, Podlutskaya V, Nagykaldi E, Gautam T, Miller RA, Sonntag WE, Csiszar A and Ungvari Z: The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: Implications for the developmental origins of cancer. Geroscience. 39:147–160. 2017. View Article : Google Scholar : PubMed/NCBI
29	Sehgal P, Kumar N, Praveen Kumar VR, Patil S, Bhattacharya A, Vijaya Kumar M, Mukherjee G and Kondaiah P: Regulation of protumorigenic pathways by insulin like growth factor binding protein2 and its association along with β-catenin in breast cancer lymph node metastasis. Mol Cancer. 12:632013. View Article : Google Scholar
30	Chua CY, Liu Y, Granberg KJ, Hu L, Haapasalo H, Annala MJ, Cogdell DE, Verploegen M, Moore LM, Fuller GN, et al: IGFBP2 potentiates nuclear EGFR-STAT3 signaling. Oncogene. 35:738–747. 2016. View Article : Google Scholar
31	Biernacka KM, Uzoh CC, Zeng L, Persad RA, Bahl A, Gillatt D, Perks CM and Holly JM: Hyperglycaemia-induced chemore-sistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer. 20:741–751. 2013. View Article : Google Scholar : PubMed/NCBI
32	Wu H, Goel V and Haluska FG: PTEN signaling pathways in melanoma. Oncogene. 22:3113–3122. 2003. View Article : Google Scholar : PubMed/NCBI
33	Shen X, Xi G, Radhakrishnan Y and Clemmons DR: PDK1 recruitment to the SHPS-1 signaling complex enhances insulin-like growth factor-i-stimulated AKT activation and vascular smooth muscle cell survival. J Biol Chem. 285:29416–29424. 2010. View Article : Google Scholar : PubMed/NCBI
34	Harris TK: PDK1 and PKB/Akt: Ideal targets for development of new strategies to structure-based drug design. IUBMB Life. 55:117–126. 2003. View Article : Google Scholar : PubMed/NCBI
35	Zhang Y, Wang SJ, Han ZH, Li YQ, Xue JH, Gao DF, Wu XS and Wang CX: PI3K/AKT signaling pathway plays a role in enhancement of eNOS activity by recombinant human angiotensin converting enzyme 2 in human umbilical vein endothelial cells. Int J Clin Exp Pathol. 7:8112–8117. 2014.
36	Li H, Zeng J and Shen K: PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet. 290:1067–1078. 2014. View Article : Google Scholar : PubMed/NCBI
37	Goschzik T, Gessi M, Denkhaus D and Pietsch T: PTEN mutations and activation of the PI3K/Akt/mTOR signaling pathway in papillary tumors of the pineal region. J Neuropathol Exp Neurol. 73:747–751. 2014. View Article : Google Scholar : PubMed/NCBI
38	Lv D, Liu J, Guo L, Wu D, Matsumoto K and Huang L: PRAS40 deregulates apoptosis in Ewing sarcoma family tumors by enhancing the insulin receptor/Akt and mTOR signaling pathways. Am J Cancer Res. 6:486–497. 2016.PubMed/NCBI
39	Havel JJ, Li Z, Cheng D, Peng J and Fu H: Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway. Oncogene. 34:1487–1498. 2015. View Article : Google Scholar
40	Bhattacharya K, Maiti S and Mandal C: PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor. Oncogenesis. 5:e2272016. View Article : Google Scholar : PubMed/NCBI
41	Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK and Sawyers CL: Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci USA. 104:5563–5568. 2007. View Article : Google Scholar : PubMed/NCBI
42	Ahani N, Karimi Arzenani M, Shirkoohi R, Rokouei M, Alipour Eskandani M and Nikravesh A: Expression of insulin-like growth factor binding protein-2 (IGFBP-2) gene in negative and positive human cytomegalovirus glioblastoma multiforme tissues. Med Oncol. 31:8122014. View Article : Google Scholar
43	Mireuta M, Darnel A and Pollak M: IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription. Growth Factors. 28:243–255. 2010. View Article : Google Scholar : PubMed/NCBI