MiR-30c suppresses the proliferation, metastasis and polarity reversal of tumor cell clusters by targeting MTDH in invasive micropapillary carcinoma of the breast

Yunwei Han; Weidong Li; Renyong Zhi; Gui Ma; Ang Gao; Kailiang Wu; Hui Sun; Dan Zhao; Yiling Yang; Fangfang Liu; Feng Gu; Xiaojing Guo; Jintang Dong; Shuai Li; Li Fu

doi:10.1016/j.heliyon.2024.e33938

MiR-30c suppresses the proliferation, metastasis and polarity reversal of tumor cell clusters by targeting MTDH in invasive micropapillary carcinoma of the breast

Heliyon. 2024 Jul 2;10(13):e33938. doi: 10.1016/j.heliyon.2024.e33938. eCollection 2024 Jul 15.

Authors

Yunwei Han^{1

2

3

4

5

6}, Weidong Li^{1

2

3

4

5

6}, Renyong Zhi^{1

2

3

4

5

6}, Gui Ma^{7

8

9}, Ang Gao^{7

8

9}, Kailiang Wu^{1

2

3

4

5

6}, Hui Sun^{1

2

3

4

5

6}, Dan Zhao^{7

8

9}, Yiling Yang^{1

2

3

4

5

6}, Fangfang Liu^{1

2

3

4

5

6}, Feng Gu^{1

2

3

4

5

6}, Xiaojing Guo^{1

2

3

4

5

6}, Jintang Dong^{7

8

9}, Shuai Li^{1

2

3

4

5

6}, Li Fu^{1

2

3

4

5

6

10

11

12}

Affiliations

¹ Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
² National Clinical Research Center of Cancer, Tianjin 300060, China.
³ Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
⁴ Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China.
⁵ Ministry of Education, Breast Cancer Innovation Team of the Ministry of Education, Tianjin 300060, China.
⁶ Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Breast Cancer Research, Tianjin 300060, China.
⁷ Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
⁸ Southern University of Science and Technology, School of Medicine, 1088 Xueyuan Road, Shenzhen, Guangdong 518055, China.
⁹ Emory Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, 1365C Clifton Road, Atlanta, 30322, Georgia, USA.
¹⁰ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹¹ Gene Editing Center, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
¹² Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.

Abstract

Purpose: Invasive micropapillary carcinoma (IMPC) of the breast has a high propensity for lymphovascular invasion and axillary lymph node metastasis and displays an 'inside-out' growth pattern, but the molecular mechanism of invasion, metastasis and cell polarity reversal in IMPC is unclear.

Methods: and Patients: Cell growth curves, tumor sphere formation assays, transwell assays, mouse xenograft model and immunofluorescence were evaluated to investigate the effects of miR-30c and MTDH. Dual luciferase reporter assays was performed to confirm that the MTDH (metadherin) 3'UTR bound to miR-30c. MiRNA in situ hybridization (ISH) and immunohistochemistry (IHC) were carried out on IMPC patient tissues for miR-30c and MTDH expression, respectively.

Results: We found miR-30c as a tumor suppressor gene in cell proliferation, metastasis and polarity reversal of IMPC. Overexpression of miR-30c inhibited cell growth and metastasis in vitro and in vivo. MiR-30c could directly target the MTDH 3'UTR. MiR-30c overexpression inhibited breast cancer cell proliferation, invasion and metastasis by targeting MTDH. Moreover, miR-30c/MTDH axis could also regulate cell polarity reversal of IMPC. By ISH and IHC analyses, miR-30c and MTDH were significantly correlated with tumor size, lymph nodule status and tumor grade, the 'inside-out' growth pattern, overall survival (OS) and disease-free survival (DFS) in IMPC patients.

Conclusions: Overall, miR-30c/MTDH axis was responsible for tumor proliferation, metastasis and polarity reversal. It may provide promising therapeutic targets and prognostic biomarkers for patients with IMPC.

Keywords: Breast cancer; Invasive micropapillary carcinoma (IMPC); Metastasis; MiRNA; Polarity reversal; Proliferation.