Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer

Lan, Shenghui; Lin, Shih-Syun; Wang, Weichen; Yang, Yuchan; Lee, Jenq‐Chang; Lin, Pei‐Wen; Chu, Man-Ling; Lan, Kai; Zuchini, Roberto; Liu, Hsiao Sheng; Wu, Shan-Ying

doi:10.3389/fonc.2021.738144

Cited by 17 publications

(11 citation statements)

References 47 publications

(49 reference statements)

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“…Some studies reported that autophagy is upregulated in response to cancer treatments and protects tumor cells by increasing treatment resistance. Others reported low autophagic activity or autophagy deficiency in various cancers, including hepatoma and colorectal cancer [8,46]. Nevertheless, these findings imply that pharmacological manipulation of autophagic activity to suppress tumorigenesis is a promising anticancer strategy [44,45,[47][48][49].…”

Section: Discussionmentioning

confidence: 98%

Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1

Chen

Liu

et al. 2022

J Biomed Sci

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Background Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1 (TIMP1), an inflammatory cytokine, under serum-depleted conditions which leads to suppression of lung cancer cell metastasis has been reported. Starvation is also a stimulus of autophagic activity. Herein, we reveal that starvation activates Rab37 and induces autophagy. Methods We used an overexpression/knockdown system to determine the relationship between autophagy and Rab37 in vitro and in vivo. The autophagy activity was detected by immunoblotting, transmission electron microscope, autophagosome purification, and immunofluorescence under the confocal microscope. Lung-to-lung metastasis mouse model was used to clarify the role of autophagy and Rab37 in lung cancer. Clinical lung cancer patient specimens and an online big database were analyzed. Results Initially, we demonstrated that active-form Rab37 increased LC3-II protein level (the marker of autophagosome) and TIMP1 secretion. Accordingly, silencing of Rab37 gene expression alleviated Rab37 and LC3-II levels as well as TIMP1 secretion, and induction of autophagy could not increase TIMP1 exocytosis under such conditions. Moreover, silencing the Atg5 or Atg7 gene of lung cancer cells harboring active-mutant Rab37 (Q89L) led to decreased autophagy activity and TIMP1 secretion. In the lung-to-lung metastasis mouse model, increased TIMP1 expression accompanied by amiodarone-induced autophagy led to decreased tumor nodules and cancer cell metastasis. These phenomena were reversed by silencing the Atg5 or Atg7 gene. Notably, increasing autophagy activity alone showed no effect on TIMP1 secretion under either Rab37 or Sec22b silencing conditions. We further detected colocalization of LC3 with either Rab37 or TIMP1, identified Rab37 and Sec22b proteins in the purified autophagosomes of the lung cancer cells harboring the active-form Rab37 gene, and confirmed that these proteins are involved in the secretion of TIMP1. We reveal that autophagic activity was significantly lower in the tumors compared to the non-tumor parts and was associated with the overall lung cancer patient survival rate. Conclusions We are the first to report that autophagy plays a promoting role in TIMP1 secretion and metastasis in a Rab37-dependent manner in lung cancer cells and the lung-to-lung mouse model.

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Section: Discussionmentioning

confidence: 98%

Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1

Chen

Liu

et al. 2022

J Biomed Sci

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“…MiR-449a is considered a tumor-suppressive miRNA, and its downregulated expression has been associated with advanced clinical stage and the poor histological differentiation of CRC [ 40 , 64 ]. Recently, it has been reported that the upregulation of autophagy-dependent miR-449a suppresses CRC tumorigenesis both in vitro and in vivo [ 65 ]. Based on these findings, the ability to reactivate the expression of the tumor-suppressive miR-34a/c/miR-449a, thereby restoring their levels in CRC cells, makes AdoMet a potential therapeutic agent for colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

Borzacchiello

Tranchese

Grillo

et al. 2022

IJMS

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Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway.

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“…In addition, Liu et al identified and verified that miRNA-216-5p, miRNA-194-3p, and miRNA-3677-3p, which were included in the construction of immune correlation miRNAs prognostic signature (IAMIPS) module, not only predicted the survival of CRC patients well, but also predicted the sensitivity of chemotherapeutic drugs [ 105 ]. Lan et al analyzed autophagy-related miRNAs in tumor tissues of CRC patients and found that low expression of miRNA-449 was associated with autophagy and poor overall survival (OS) [ 106 ]. In addition, other miRNAs are studied in CRC-related cell lines.…”

Section: Mirnas and Cancer Diagnosis And Prognosismentioning

confidence: 99%

Overview of MicroRNAs as Diagnostic and Prognostic Biomarkers for High-Incidence Cancers in 2021

Sun

Zhao

Wang

et al. 2022

IJMS

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MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) about 22 nucleotides in size, which play an important role in gene regulation and are involved in almost all major cellular physiological processes. In recent years, the abnormal expression of miRNAs has been shown to be associated with human diseases including cancer. In the past ten years, the link between miRNAs and various cancers has been extensively studied, and the abnormal expression of miRNAs has been reported in various malignant tumors, such as lung cancer, gastric cancer, colorectal cancer, liver cancer, breast cancer, and prostate cancer. Due to the high malignancy grade of these cancers, it is more necessary to develop the related diagnostic and prognostic methods. According to the study of miRNAs, many potential cancer biomarkers have been proposed for the diagnosis and prognosis of diseases, especially cancer, thus providing a new theoretical basis and perspective for cancer screening. The use of miRNAs as biomarkers for diagnosis or prognosis of cancer has the advantages of being less invasive to patients, with better accuracy and lower price. In view of the important clinical significance of miRNAs in human cancer research, this article reviewed the research status of miRNAs in the above-mentioned cancers in 2021, especially in terms of diagnosis and prognosis, and provided some new perspectives and theoretical basis for the diagnosis and treatment of cancers.

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Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer

Cited by 17 publications

References 47 publications

Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1

Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

Overview of MicroRNAs as Diagnostic and Prognostic Biomarkers for High-Incidence Cancers in 2021

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