Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

Siri Amanda Tvingsholm; Malene Bredahl Hansen; Knut Kristoffer Bundgaard Clemmensen; Ditte Marie Brix; Bo Rafn; Lisa B. Frankel; Riku Louhimo; José Moreira; Sampsa Hautaniemi; Irina Gromova; Marja Jäättelä; Tuula Kallunki

doi:10.1038/s41389-017-0014-6

Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

Siri Amanda Tvingsholm, Malene Bredahl Hansen, Knut Kristoffer Bundgaard Clemmensen, Ditte Marie Brix, Bo Rafn, Lisa B. Frankel, Riku Louhimo, José Moreira, Sampsa Hautaniemi, Irina Gromova, Marja Jäättelä^*, Tuula Kallunki

^*Corresponding author for this work

Department of Drug Design and Pharmacology

14 Citations (Scopus)

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Abstract

Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.

Original language	English
Article number	14
Journal	Oncogene
Volume	7
Issue number	2
Pages (from-to)	1-15
Number of pages	15
ISSN	0950-9232
DOIs	https://doi.org/10.1038/s41389-017-0014-6
Publication status	Published - 2018

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Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1Final published version, 2.97 MBLicence: CC BY

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Tvingsholm, S. A., Hansen, M. B., Clemmensen, K. K. B., Brix, D. M., Rafn, B., Frankel, L. B., Louhimo, R., Moreira, J., Hautaniemi, S., Gromova, I., Jäättelä, M., & Kallunki, T. (2018). Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1. Oncogene, 7(2), 1-15. Article 14. https://doi.org/10.1038/s41389-017-0014-6

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title = "Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1",

abstract = "Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.",

author = "Tvingsholm, {Siri Amanda} and Hansen, {Malene Bredahl} and Clemmensen, {Knut Kristoffer Bundgaard} and Brix, {Ditte Marie} and Bo Rafn and Frankel, {Lisa B.} and Riku Louhimo and Jos{\'e} Moreira and Sampsa Hautaniemi and Irina Gromova and Marja J{\"a}{\"a}ttel{\"a} and Tuula Kallunki",

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doi = "10.1038/s41389-017-0014-6",

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T1 - Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

AU - Tvingsholm, Siri Amanda

AU - Hansen, Malene Bredahl

AU - Clemmensen, Knut Kristoffer Bundgaard

AU - Brix, Ditte Marie

AU - Rafn, Bo

AU - Frankel, Lisa B.

AU - Louhimo, Riku

AU - Moreira, José

AU - Hautaniemi, Sampsa

AU - Gromova, Irina

AU - Jäättelä, Marja

AU - Kallunki, Tuula

PY - 2018

Y1 - 2018

N2 - Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.

AB - Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.

U2 - 10.1038/s41389-017-0014-6

DO - 10.1038/s41389-017-0014-6

M3 - Journal article

C2 - 29396433

AN - SCOPUS:85041561580

SN - 0950-9232

VL - 7

SP - 1

EP - 15

JO - Oncogene

JF - Oncogene

IS - 2

M1 - 14

ER -

Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

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