Lin28B Is an Oncofetal Circulating Cancer Stem Cell-Like Marker Associated with Recurrence of Hepatocellular Carcinoma

Cheng, Shu Wen; Tsai, Hung Wen; Lin, Yih Jyh; Cheng, Pin Nan; Chang, Yu Chung; Yen, Chia Jui; Huang, Hsuan; Chuang, Yun Pei; Chang, Ting Tsung; Lee, Chung Ta; Chao, An-Ning; Chou, Cheng Yang; Chan, Shih Huang; Chow, Nan Haw; Ho, Chung Liang

doi:10.1371/journal.pone.0080053

Cited by 53 publications

(54 citation statements)

References 42 publications

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“…However, this study demonstrated a novel mechanism, indicating that activation of IKKb, an inflammatory kinase in the NF-kB pathway, was strongly correlated with the expression of stemness genes, especially LIN28B in human breast cancer cell lines or tissues. Previous studies also showed that LIN28B promoted tumor cell transformation (23,24) and had a functional role in the maintenance of CSCs (25,26). Consistent with these findings, our experiment results showed that expression of LIN28B was highly positively correlated with tumor progress in human breast cancer patients, indicating that there were high levels of LIN28B in stage 3 patients with lymphatic metastasis of breast cancer.…”

Section: Discussionsupporting

confidence: 90%

“…In fact, it has been reported that LIN28A/LIN28B can promote transformation by repressing let-7 miRNAs, and that activation of LIN28A/LIN28B occurs in many different human tumors with a frequency of approximately 15% (23,24). Recent studies have also suggested that LIN28 plays an important role in the maintenance of CSCs (25,26) and Wnt signaling could directly activate LIN28 to augment breast cancer stem cell expansion (27).…”

Section: Introductionmentioning

confidence: 99%

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IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

et al. 2015

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Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKb) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKb, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAimediated silencing of LIN28B or pharmacologic inhibition of IKKb was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/ TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

et al. 2015

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“…LIN28A and LIN28B function as oncoproteins that promote cell proliferation and transformation (2–5). LIN28A/LIN28B expression has also been found in diverse malignancies and is associated with decreased survival in ovarian, colon and hepatocellular cancer (3, 6, 7). MYC induces LIN28B expression in multiple tumor models by binding to the LIN28B promoter (5).…”

Section: Introductionmentioning

confidence: 99%

MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC

Alam

Ahmad

Rajabi

et al. 2015

Molecular Cancer Research

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The LIN28B→let-7 pathway contributes to regulation of the epithelial-mesenchymal transition (EMT) and stem cell self-renewal. The oncogenic MUC1-C transmembrane protein is aberrantly overexpressed in lung and other carcinomas; however, there is no known association between MUC1-C and the LIN28B→let-7 pathway. Here in non-small cell lung cancer (NSCLC), silencing MUC1-C downregulates the RNA binding protein LIN28B and coordinately increases the miRNA let-7. Targeting MUC1-C function with a dominant-negative mutant or a peptide inhibitor provided confirming evidence that MUC1-C induces LIN28B→let-7 signaling. Mechanistically, MUC1-C promotes NF-κB p65 chromatin occupancy of the LIN28B first intron and activates LIN28B transcription, which is associated with suppression of let-7. Consistent with let-7-mediated inhibition of HMGA2 transcripts, targeting of MUC1-C also decreases HMGA2 expression. HMGA2 has been linked to stemness, and functions as a competing endogenous RNA (ceRNA) of let-7-mediated regulation of the TGFβ co-receptor TGFBR3. Accordingly, targeting MUC1-C suppresses HMGA2 mRNA and protein, which is associated with decreases in TGFBR3, reversal of the EMT phenotype and inhibition of self-renewal capacity. These findings support a model in which MUC1-C activates the ⇑LIN28B→⇓let-7→⇑HMGA2 axis in NSCLC and thereby promotes EMT traits and stemness.

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“…High OCT4 expression also predicts unfavorable clinical outcome in medulloblastoma and gastric cancer [9,10]. Lin28b, an RNA-binding protein, has been implicated in the genesis of Wilms tumor [11] and gliomas [12], as well as recurrence of hepatocellular carcinoma [13], and aggressiveness of breast carcinoma [14]. Altogether, these and other recent studies highlight a contribution of pluripotency-related genes toward a more aggressive tumor phenotype, supporting their involvement in the acquisition of a stem-like state in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Santos

Silva

Rodini

et al. 2015

Stem Cells and Development

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Misexpression of stem cell-related genes may occur in some cancer cells, influencing patient's prognosis. This is the case of medulloblastoma, a common and clinically challenging malignant tumor of the central nervous system, where expression of the pluripotency factor, OCT4, is correlated with poor survival. A downstream target of OCT4, L1TD1 (LINE-1 type transposase domain-containing protein 1 family member), encodes a novel embryonic stem cell (ESC)-related protein involved in pluripotency and self-renewal of ESCs. L1TD1 is still poorly characterized and its expression pattern and function in cancer cells are virtually unknown. Although normally restricted to non-neoplastic undifferentiated cells and germ cells, we found that high L1TD1 expression also occurs in medulloblastoma cells, reaching levels similar to those found in ESCs, and is correlated with poor prognosis. Conversely to what is reported during normal cell differentiation, when differentiated cells remain healthy, despite L1TD1 downregulation, depletion of L1TD1 protein levels by targeted gene silencing significantly reduced medulloblastoma cell viability, inhibiting cell proliferation and inducing apoptosis. More strikingly, L1TD1 depletion downregulated expression of the neural stem cell markers, CD133 and Nestin, inhibited neurosphere generation capability, and sensitized medulloblastoma cells to temozolomide and cisplatin, two chemotherapeutic agents of clinical relevance in medulloblastoma treatment. Our findings provide insights about the contribution of pluripotency-related genes to a more aggressive tumor phenotype through their involvement in the acquisition of stem-like properties by cancer cells and point out L1TD1 as a potential therapeutic target in malignant brain tumors.

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Lin28B Is an Oncofetal Circulating Cancer Stem Cell-Like Marker Associated with Recurrence of Hepatocellular Carcinoma

Cited by 53 publications

References 42 publications

IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis

MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

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