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The multifaceted role of MUC1 in tumor therapy resistance

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Abstract

Tumor therapeutic resistances are frequently linked to the recurrence and poor prognosis of cancers and have been a key bottleneck in clinical tumor treatment. Mucin1 (MUC1), a heterodimeric transmembrane glycoprotein, exhibits abnormally overexpression in a variety of human tumors and has been confirmed to be related to the formation of therapeutic resistance. In this review, the multifaceted roles of MUC1 in tumor therapy resistance are summarized from aspects of pan-cancer principles shared among therapies and individual mechanisms dependent on different therapies. Concretely, the common mechanisms of therapy resistance across cancers include interfering with gene expression, promoting genome instability, modifying tumor microenvironment, enhancing cancer heterogeneity and stemness, and activating evasion and metastasis. Moreover, the individual mechanisms of therapy resistance in chemotherapy, radiotherapy, and biotherapy are introduced. Last but not least, MUC1-involved therapy resistance in different types of cancers and MUC1-related clinical trials are summarized.

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Abbreviations

ABC:

ATP-binding cassette

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ADCs:

Antibody-drug conjugates

AML:

Acute myeloid leukemia

APCs:

Antigen-presenting cells

BiTEs:

Bispecific T cell engagers

CAR-NK:

Chimeric antigen receptor NK cell

CAR-T:

Chimeric antigen receptor T cell

CA242:

Cancer antigen 242

CD:

Intracellular segment

CLRs:

C-type lectin receptors

CRC:

Colorectal cancer

CRDs:

Carbohydrate recognition domains

CRPC:

Castration-resistant prostate cancer

CSCs:

Cancer stem cells

CTGF/CCN2:

Connective tissue growth factor

DCs:

Dendritic cells

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

DSB:

Double-strand break

EA:

Esophageal adenocarcinoma

ECM:

Extracellular matrix

ECM1:

Extracellular matrix protein 1

ED:

Extracellular segment

EMT:

Epithelial-mesenchymal transition

ER:

Estrogen receptor

ERK:

Extracellular signal-regulated kinase

ESCC:

Esophageal squamous cell carcinoma

EVs:

Extracellular vesicles

EZH2:

Enhancer of zeste protein-2

FDA:

Food and drug administration

GMLHN:

Genistein-miRNA-29b-loaded hybrid nanoparticles

GSH:

Glutathione

HCC:

Hepatocellular carcinoma

HER2:

Human epidermal growth factor receptor-2

HIF:

Hypoxia-inducible factors

HNSCC:

Head and neck squamous cell carcinoma

HUVECs:

Human umbilical vein endothelial cells

HzMUC1:

Humanized MUC1

ICIs:

Immune checkpoint inhibitors

iDCs:

Immature DCs

IFITM1:

Interferon-induced transmembrane protein 1

IFN:

Inflammatory interferon

LEN:

Lenalidomide

LNM:

Lymph node metastasis

mAb:

Monoclonal antibody

MAFMILHNs:

MUC1-aptamer-functionalized miRNA-29b-loaded hybrid nanoparticles

MDR:

Multi-drug resistance

MDSCs:

Myeloid-derived suppressor cells

MED:

Minimum effective dose

MGL:

Macrophage galactose lectin

MM:

Multiple myeloma

MMAE:

Monomethyl auristatin E

MMP:

Matrix metalloproteinase

MTD:

Maximum tolerated dose

MUC1:

Mucin1

MUC1-C:

MUC1 carboxyl subunit

MUC1-CD:

MUC1 cytoplasmic domain

MUC1-N:

MUC1 amino subunits

NEPC:

Neuroendocrine prostate cancer

NF-κB:

Nuclear factor kappa B

NPC:

Nasopharyngeal cancer

NSCLC:

Non-small cell lung cancer

OT-MUC1:

Onco-tethered MUC1

PC:

Pancreatic cancer

PDA:

Pancreatic ductal adenocarcinoma

PDGFA:

Platelet-derived growth factor-A

PE:

Pseudomonas exotoxin A

PFS:

Progression-free survival

PMI:

Postpartum mammary gland involution

PPI:

Polyphyllin I

PPP:

Phosphonates pathway

PRC1:

Polycomb repressive complex 1

PSCA:

Prostate stem cell antigen

Ptgs2/PTGS2:

Promoter of COX-2 gene

PTX:

Paclitaxel

PUBNs:

Papillary urothelial bladder neoplasms

RHD:

Rel homology domain

SEA:

Sperm protein, enterokinase, and agrin

sialyl-Tn, sTn:

Neu5Acα2,6-GalNAcα-O-Ser/Thr

SREBP1:

Sterol regulatory element binding protein 1

TA:

Tumor-associated

TA MUC1:

Tumor-associated MUC1

TACA:

Tumor-associated carbohydrate antigens

TAMs:

TUMOR-associated macrophages

TCF4:

Transcription factor 4

TF:

Galβ1,3-GalNAcα-O-Ser/Thr

TFs:

Transcription factors

TIME:

Tumor immune microenvironment

TM:

Transmembrane segment

Tn:

GalNAcα-O-Ser/Thr

TNBC:

Triple-negative breast cancer

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

Tregs:

Regulatory T cells

TSGs:

Tumor-suppressor genes

VLPs:

Virus-like particles

VNTR:

Variable-number tandem repeat

xCT:

X-cystine/glutamate transporter

Y-90:

Yttrium-90

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Acknowledgements

Weiqiu Jin and Mengwei Zhang would like to thank Dr. Quanfu Li for his instruction during their Research-based Learning program in Prof. Huang’s laboratory during September 2020 to March 2021. Weiqiu Jin would also like to show his great gratitude to Dr. Ni yingyin in Huang’s lab, who gave important suggestions to this review. Figures 3 and 4 are prepared with biorender.com.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Weiqiu Jin and Mengwei Zhang have contribute equally to this work.

Authors and Affiliations

  1. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China

    Weiqiu Jin & Qingquan Luo

  2. Department of Histoembryology, Genetics and Developmental Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Weiqiu Jin, Mengwei Zhang & Lei Huang

  3. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Mengwei Zhang

  4. Department of Bioengineering, School of Engineering and Science, University of Pennsylvania, Philadelphia, 19104, USA

    Changzi Dong

  5. Innovative Research Team of High-Level Local Universities in Shanghai, Shanghai, China

    Lei Huang

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Contributions

Weiqiu Jin, Mengwei Zhang, and Changzi Dong wrote the main manuscript text. Changzi Dong prepared figure 2. Weiqiu Jin prepared other figures. Lei Huang and Qingquan Luo supervised the writting. All authors reviewed the manuscript.

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Correspondence to Lei Huang or Qingquan Luo.

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Jin, W., Zhang, M., Dong, C. et al. The multifaceted role of MUC1 in tumor therapy resistance. Clin Exp Med 23, 1441–1474 (2023). https://doi.org/10.1007/s10238-022-00978-y

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