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Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression

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Abstract

Mucins are high-molecular-weight glycoproteins dysregulated in aggressive cancers. The role of mucins in disease progression, tumor proliferation, and chemotherapy resistance has been studied extensively. This article provides a comprehensive review of mucin’s function as a physical barrier and the implication of mucin overexpression in impeded drug delivery to solid tumors. Mucins regulate the epithelial to mesenchymal transition (EMT) of cancer cells via several canonical and non-canonical oncogenic signaling pathways. Furthermore, mucins play an extensive role in enriching and maintaining the cancer stem cell (CSC) population, thereby sustaining the self-renewing and chemoresistant cellular pool in the bulk tumor. It has recently been demonstrated that mucins regulate the metabolic reprogramming during oncogenesis and cancer progression, which account for tumor cell survival, proliferation, and drug-resistance. This review article focuses on delineating mucin’s role in oncogenic signaling and aberrant regulation of gene expressions, culminating in CSC maintenance, metabolic rewiring, and development of chemoresistance, tumor progression, and metastasis.

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Abbreviations

ALDH:

aldehyde dehydrogenase

AML:

acute myeloid leukemia

CSC:

cancer stem cells

EGFR:

epidermal growth factor receptor

EMT:

epithelial-mesenchymal transition

FAK:

focal adhesion kinase

FOXO3:

forkhead box O-3

hCNT1:

human concentrative nucleoside transporter 1

HER2:

human epidermal growth factor receptor 2

HIF-1α:

hypoxia-inducible factor 1, alpha

JNK1/2:

c-Jun N-terminal kinases

Lgr5:

leucine-rich-repeat-containing G protein-coupled receptor 5

LIMO2:

LIM domain only 2

LRP6:

low density lipoprotein receptor protein 6

LSC:

leukemia stem cells

MDR:

multiple drug resistance

MKK7:

mitogen-activated protein kinase kinases 7

mTORC1:

mammalian target of rapamycin complex 1

NFkB:

nuclear factor-kappa B

PTX:

paclitaxel

RCC:

renal cell carcinoma

SP:

side population

STAT3:

signal transducer and activator of transcription 3

TGFβ:

transforming growth factor-beta

TGFβR I/ II:

transforming growth factor-beta type I/II receptor

TIGAR:

TP53-induced glycolysis and apoptosis regulator

TNBC:

triple negative breast cancer

5FU:

5-Fluorouracil

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Acknowledgements

We thank Kavita Mallya and Corinn E Grabow for their support.

Funding

The authors in this article were supported primarily by the following grants from the National Institutes of Health P01 CA217798, R01 CA210637, R01 CA183459, R01 CA195586, R01 CA201444, R01 CA228524, F99 CA234962, U01 CA200466, and U01 CA210240, and the Nebraska Department of Health and Human Services LB595.

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  1. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA

    Saravanakumar Marimuthu, Sanchita Rauth, Koelina Ganguly, Chunmeng Zhang, Imayavaramban Lakshmanan, Surinder K. Batra & Moorthy P. Ponnusamy

  2. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Surinder K. Batra & Moorthy P. Ponnusamy

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  1. Saravanakumar Marimuthu
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SM, SR, CZ, and KG, collected the related literature and drafted the manuscript. SM, SR, CZ, KG, IL, MPP, and SKB participated in the manuscript’s draft. All authors have read and approved the final manuscript.

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Correspondence to Surinder K. Batra or Moorthy P. Ponnusamy.

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SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors disclosed no potential conflicts of interest.

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Marimuthu, S., Rauth, S., Ganguly, K. et al. Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression. Cancer Metastasis Rev 40, 575–588 (2021). https://doi.org/10.1007/s10555-021-09959-1

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