CUL4B contributes to cancer stemness by repressing tumor suppressor miR34a in colorectal cancer

Li, Yanjun; Hu, Huili; Wang, Yuxing; Fan, Yujia; Yang, Yang; Guo, Beibei; Xie, Xueyong; Lian, Jiabei; Jiang, Baichun; Han, Bo; Wang, Yanlei; Shao, Changshun; Gong, Yaoqin

doi:10.1038/s41389-020-0206-3

Cited by 25 publications

(23 citation statements)

References 45 publications

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“…miR-34a is down-regulated in many cancers [ 43 , 53 – 55 ], and there are several hypotheses that explain this down-regulation [ 44 , 56 – 58 ]. By leveraging the TCGA dataset, we demonstrated two possible mechanisms of miR-34a-5p down-regulation in cancer.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2021

J Exp Clin Cancer Res

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Background MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. Methods Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. Results Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. Conclusions Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2021

J Exp Clin Cancer Res

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“…Lastly, our work demonstrates a role of miR-34a in maintaining tumor immunity, as inhibition of miR-34a resulted in a decreased in percentage of antiin ammatory (M2-like) TAMs and PDL1 + TAMs, which are reported to have pro-tumorigenic activity (57,58). miR-34a is down-regulated in many cancers (47,(59)(60)(61), and there are several hypotheses that explain this down-regulation (48,(62)(63)(64). By leveraging the TCGA dataset, we demonstrated two possible mechanisms of miR-34a down-regulation in cancer.…”

Section: Discussionmentioning

confidence: 64%

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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Background: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34a family is thought to play a role in tumor suppression, but the exact mechanism of action in HNSCC is not well understood. In addition, miR-34a is generally down-regulated HNSCC, but the role of chromosomal changes and mutation status on miR-34a expression remain unknown. Methods: Differential expression of miR-34a-3p, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, and rescue experiments. Lastly, mouse xenograft and locked nucleic acid anti-miRs were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo.Results: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. We found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Moreover, ectopic expression of miR-34a reduces HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells, myeloid cells, and regulatory T cells. Consistent with these findings, inhibition of miR-34a in an in vivo model of HNSCC leads to an increased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. Conclusions: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity, and could potentially represent a new therapeutic approach for HNSCC.

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“…CUL4B has been also reported to be elevated in several other solid cancers 5 . In colorectal cancer, CUL4B was found elevated, and its knockdown led to the suppression of colorectal cancer cell proliferation, metastasis and sphere formation 10 . In gastric cancer, CUL4B was also found overexpressed, and CUL4B overexpression was positively correlated with poor prognosis of gastric cancer patients 11 .…”

Section: Discussionmentioning

confidence: 95%

“…And overexpressed CUL4B promoted prostate cancer cell proliferation and aggressiveness by regulating miR‐33b/C‐MYC axis 9 . In addition, CUL4B was also reported to promote the development of colon cancer by maintaining the tumor stem‐like features through repressing miR34a expression, and elevated CUL4B was also confirmed in the tumor tissues of colon cancer, which also indicated a poor overall survival for colon cancer patients 10 …”

Section: Introductionmentioning

confidence: 88%

Cullin 4B regulates cell survival and apoptosis in clear cell renal cell carcinoma as a target of microRNA‐217

Yang

Wang

Mao

et al. 2020

The Kaohsiung J of Med Scie

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Cullin 4B (CUL4B) was reported to be closely related to the progression of some tumors, but its function in clear cell renal cell carcinoma (ccRCC) has not been reported. Our present study found CUL4B was upregulated in ccRCC, and CUL4B knockdown markedly inhibited ccRCC cell growth and induced apoptosis. In addition, CUL4B knockdown markedly inhibited antiapoptotic proteins' expression in ccRCC cells, including Mcl‐1 and Bcl‐2, and silenced CUL4B also induced the cleavages of PARP, an important index of apoptosis. We also confirmed microRNA‐217 (miR‐217) was downregulated in ccRCC tumor tissues, and negatively correlated with CUL4B expression. Further investigations revealed miR‐217 targeted CUL4B and markedly inhibited its expression in ccRCC cells. In addition, overexpression of miR‐217 by mimics significantly suppressed ccRCC cell growth. In contrast, enforced expression of CUL4B significantly abolished miR‐217‐induced cell survival inhibition in ccRCC cells. In conclusion, our present results suggested targeting miR‐217‐CUL4B axis would be a promising strategy for ccRCC treatment.

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CUL4B contributes to cancer stemness by repressing tumor suppressor miR34a in colorectal cancer

Cited by 25 publications

References 45 publications

Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion

Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cullin 4B regulates cell survival and apoptosis in clear cell renal cell carcinoma as a target of microRNA‐217

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