Journal of Shanghai Jiao Tong University (Medical Science) >
Screening of MUCIN family members synergistic with MUC1 in tumor chemoresistance
Received date: 2021-12-13
Accepted date: 2022-03-09
Online published: 2022-06-07
Supported by
National Natural Science Foundation of China(81874197);The 13th Innovation Training Program for Students of Shanghai Jiao Tong University School of Medicine(1319014);Experimental Technical Team Construction Project of Shanghai Municipal Education Commission(BJ1-3000-19-0135)
Objective ·To screen partners of mucin 1 (MUC1) in MUCIN family members that involve in chemoresistance. Methods ·Two pairs of cell lines were employed, including HeLa229/TR-CasCTL and HeLa229/TR-CasMUC1, and HeLa229/P and paclitaxel-resistant cell HeLa229/TR. Firstly, the cells were employed to detect the mRNA levels of MUCINs by quantitative real-time PCR (qPCR). The correlation of mRNA levels between MUC1 and MUCINs was analyzed. Then, Western blotting was performed to detect the protein levels of the selected MUCINs to get the proteins correlated with MUC1 at both mRNA and protein levels. IC50 assay was further employed to detect the role of target protein in paclitaxel resistance by knockdown of the gene through shRNA in HeLa229/TR cells. The mean expression levels of MUC1 and MUC13 in a variety of cancer tissues were further explored in the GEPIA database. The R2 database was further employed to detect the linear correlation of the expression between MUC1 and MUC13 in cervical, colon and pancreatic cancer tissues. Finally, the expression of MUC1 and MUC13 was analyzed by the Kaplan-Meier Plotter database in relation to the survival rate of patients with gastric cancer. Results ·The detection of qPCR showed that MUC13 and MUC18 exhibited correlation with MUC1 at the mRNA level in MUCIN family members. Western blotting showed that only MUC13 protein was up-regulated with the up-regulation of MUC1, while down-regulated with the silence of MUC1. IC50 assay displayed that silencing of MUC13 in HeLa229/TR decreased IC50 to paclitaxel. By searching the GEPIA database, the expression levels of MUC1 and MUC13 were simultaneous high or low in a variety of cancer tissues. From the R2 database, MUC1 and MUC13 showed a positive linear correlation in cervical, colon and pancreatic cancer tissues. In addition, the negative relationship of the expression of MUC1 and MUC13 and survival rate of patients with gastric cancer from the Kaplan-Meier Plotter database was observed. Conclusion ·MUC13 is a partner for MUC1 in promoting tumor chemoresistance. The expression levels of MUC1 and MUC13 are negatively related with the survival rate of cancer patients. It's feasible for joint inhibiting MUC1 and MUC13 to overcome chemoresistance.
Key words: MUCIN family; mucin 1 (MUC1); synergistic effect; chemoresistance
Kairan TANG , Qiong WU , Sijia HUANG , Xudong QIU , Wenyan LI , Huayun DENG , Lei HUANG . Screening of MUCIN family members synergistic with MUC1 in tumor chemoresistance[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022 , 42(9) : 1288 -1295 . DOI: 10.3969/j.issn.1674-8115.2022.09.015
1 | ZHENG H C. The molecular mechanisms of chemoresistance in cancers[J]. Oncotarget, 2017, 8(35): 59950-59964. |
2 | JIN W, LIAO X D, LV Y P, et al. MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner[J]. Cell Death Dis, 2017, 8(8): e2980. |
3 | KUFE D W. Mucins in cancer: function, prognosis and therapy[J]. Nat Rev Cancer, 2009, 9(12): 874-885. |
4 | HANISCH F G, MüLLER S. MUC1: the polymorphic appearance of a human mucin[J]. Glycobiology, 2000, 10(5): 439-449. |
5 | KUFE D W. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches[J]. Oncogene, 2013, 32(9): 1073-1081. |
6 | NATH S, MUKHERJEE P. MUC1: a multifaceted oncoprotein with a key role in cancer progression[J]. Trends Mol Med, 2014, 20(6): 332-342. |
7 | NATH S, DANESHVAR K, ROY L D, et al. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes[J]. Oncogenesis, 2013, 2: e51. |
8 | THULASIRAMAN P, JOHNSON A B. Regulation of Mucin 1 and multidrug resistance protein 1 by honokiol enhances the efficacy of doxorubicin-mediated growth suppression in mammary carcinoma cells[J]. Int J Oncol, 2016, 49(2): 479-486. |
9 | BHATIA R, GAUTAM S K, CANNON A, et al. Cancer-associated mucins: role in immune modulation and metastasis[J]. Cancer Metastasis Rev, 2019, 38(1/2): 223-236. |
10 | TAMURA Y, HIGASHI M, KITAMOTO S, et al. MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer[J]. PLoS One, 2012, 7(11): e49251. |
11 | WANG H P, JIN S J, LU H L, et al. Expression of survivin, MUC2 and MUC5 in colorectal cancer and their association with clinicopathological characteristics[J]. Oncol Lett, 2017, 14(1): 1011-1016. |
12 | RAKHA E A, BOYCE R W G, ABD EL-REHIM D, et al. Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer [J]. Mod Pathol, 2005, 18(10): 1295-1304. |
13 | LV Y P, CANG W, LI Q F, et al. Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer[J]. Oncogenesis, 2019, 8(12): 70. |
14 | CASCIO S, FINN OJ. Intra- and extra-cellular events related to altered glycosylation of MUC1 promote chronic inflammation, tumor progression, invasion, and metastasis[J]. Biomolecules, 2016, 6(4): E39. |
15 | GROVER P, NATH S, NYE M D, et al. SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line[J]. Oncotarget, 2018, 9(6): 6897-6910. |
16 | BOUILLEZ A, RAJABI H, PITRODA S, et al. Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas[J]. Cancer Res, 2016, 76(6): 1538-1548. |
17 | TIEMIN P, FANZHENG M, PENG X, et al. MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways[J]. J Hepatol, 2020, 72(4): 761-773. |
18 | KUMARI S, KHAN S, GUPTA S C, et al. MUC13 contributes to rewiring of glucose metabolism in pancreatic cancer[J]. Oncogenesis, 2018, 7(2): 19. |
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