Uncovering the roles of long non-coding RNAs in cancer stem cells
- Xiaoxing Huang†1,
- Ruijing Xiao†1,
- Shan Pan1,
- Xiangyong Yang2,
- Wen Yuan1,
- Zhenbo Tu1,
- Ming Xu1,
- Yufan Zhu1,
- Qian Yin1,
- Yingjie Wu1,
- Weidong Hu3,
- Liang Shao4,
- Jie Xiong1 and
- Qiuping Zhang1Email author
© The Author(s). 2017
Received: 6 November 2016
Accepted: 23 February 2017
Published: 28 February 2017
Cancer has been a major public health problem that has threatened human life worldwide throughout history. The main causes that contribute to the poor prognosis of cancer are metastasis and recurrence. Cancer stem cells are a group of tumor cells that possess self-renewal and differentiation ability, which is a vital cause of cancer metastasis and recurrence. Long non-coding RNAs refer to a class of RNAs that are longer than 200 nt and have no potential to code proteins, some of which can be specifically expressed in different tissues and different tumors. Long non-coding RNAs have great biological significance in the occurrence and progression of cancers. However, how long non-coding RNAs interact with cancer stem cells and then affect cancer metastasis and recurrence is not yet clear. Therefore, this review aims to summarize recent studies that focus on how long non-coding RNAs impact tumor occurrence and progression by affecting cancer stem cell self-renewal and differentiation in liver cancer, prostate cancer, breast cancer, and glioma.
KeywordsLong non-coding RNAs Cancer stem cells Self-renewal Malignant transformation Tumor metastasis Tumor recurrence
According to the result of Human Genome Project, only approximately 20 thousand genes of human genome have the encoding protein ability . At the same time, only 5–7% of human genes can be stably transcribed. The vast majority of RNAs are therefore unable to be translated into protein and are termed non-coding RNAs [2–4]. Non-coding RNAs used to be considered by scientists to be “junk RNAs”; however, an increasing body of evidence suggests that non-coding RNAs play an important role in both physiological and pathological conditions [5–7].
The tumor complex contains heterogeneous cells of different differentiation degrees . Cancer stem cells (CSCs) are a group of tumor cells that have differentiation and self-renewal ability . In 2003, Visvader and Linderman first defined CSCs in acute myeloid leukemia . Recently, more research has shown that CSCs are involved in the occurrence, development, invasion, metastasis, and drug resistance of numerous solid tumors [27–30], which is closely related to poor tumor prognosis. Removal of CSCs is considered a new hope for the eradication of malignant tumors and the prevention of tumor recurrence .
Some research has demonstrated that the aberrant expression of LncRNAs in malignant tumors is closely related to the function of CSCs. Numerous LncRNAs modulate the functions of CSCs by regulating OCT4, SOX2, KLF4, and other classic stem cell-related pathways [32–34]. In addition, other LncRNAs contribute to CSC functions and tumor occurrence and development by inhibiting the miR-200 family, let-7, miR-140, and other miRNAs [35–37]. In recent years, research regarding LncRNAs and CSCs gradually became important to cancer researchers. This review aims to summarize the current research status of LncRNA and CSCs in different tumors and to explore the significance of LncRNA in the removal of CSCs and tumor therapy.
Hepatocellular carcinoma (HCC) is a global health problem and is ranked sixth worldwide for malignant tumors . Over 700,000 patients are newly diagnosed with HCC every year . Thus, the mechanisms of HCC development and progression and therapeutic targets and methods have been the focus of scientists. Increasingly, research suggests that LncRNAs participate in the self-renewal and proliferation of HCC stem cells by different mechanisms and play important roles in HCC deterioration.
In addition, Li et al. reported that LncRNA HOTAIR can inhibit the trimethylation level of its downstream histone H3K36 by suppressing the expression of SETD2, which can enhance the malignant proliferation of HCC stem cells and accelerate the progression of HCC by affecting the repair of aged histones, microsatellite stability, and cell cycle-related genes  (Fig. 2 (Part 2)). Thus, it can be seen that LncRNA can enhance the malignant transformation of HCC stem cells by regulating the abnormal modification of histones. At the same time, scientists have reported that LncRNAs can accelerate the development and progression of HCC by altering the classic signaling pathways that are related to HCC stem cells. For instance, lncTCF7 can alter the expression of TCF7 by recruiting SWI/SNF to combine with the TCF7 promoter region, which could activate the WNT signaling pathways and accelerate self-renewal of HCC stem cells and the deterioration of HCC  (Fig. 2 (Part 3)). LncRNA DILC can inhibit the self-renewal of HCC stem cells by blocking the HCC autocrine IL-6/STAT3 signaling pathway  (Fig. 2 (Part 4)). Moreover, LncRNAs can also take part in regulating the self-renewal and proliferation of HCC stem cells via inhibiting the combination of microRNA and target genes, playing a role in secretion in the tumor microenvironment [48, 49]. In conclusion, the results of several studies have indicated that LncRNAs play important roles in the malignant transformation of HCC stem cells, providing a new possibility for HCC clinical treatment.
Breast cancer has long been a serious threat to the health of women around the world . With in-depth studies on the occurrence and development of breast cancer, researchers have found that breast CSCs appear resistant to chemotherapy, radiotherapy, and hypoxia. Furthermore, breast CSCs exhibit high tumorigenicity and invasiveness, which are crucial to the occurrence, development, metastasis, and recurrence of breast cancer. According to the reports, LncRNAs can affect the characteristics of breast CSCs through various pathways, and have a great effect on breast cancer progression. During the occurrence and progression of breast cancer, the epithelial mesenchymal transition (EMT) is closely related to the function of breast CSCs, and numerous LncRNAs can promote or inhibit the metastasis and invasion of breast cancer cells by inducing or inhibiting EMT .
In general, LncRNAs typically affect the characteristics of breast CSCs by influencing the EMT-related signaling pathways. These research achievements provide a broader space for us to study on breast CSCs. During the course of breast cancer treatment, LncRNAs could be used as new markers for early diagnosis and prognosis forecast in the future. In addition, they may also be a new therapeutic target and provide new ideas for breast cancer targeted therapy.
Research regarding the effect and mechanism of LncRNAs on CSCs’ self-renewal and malignant transformation is still in the initial stages. However, the existing research indicates that the aberrant expression of LncRNAs plays a key role in the self-renewal and malignant transformation of CSCs and tumor progression. At the present stage, research regarding the effect of LncRNAs on CSCs mainly concentrates on HCC, prostate cancer, breast cancer, and glioma, and researchers have found that the mechanisms of LncRNAs in different tumors are not consistent (see Additional file 1), which include changes in histone modification, the regulation of classic stem cell-related signaling pathways such as SOX2/KLF4, the induction of EMT, and the inhibition of miRNA function. These findings indicate that LncRNAs have strong biological effects on the function and mechanisms of CSCs. Additionally, numerous studies have found that LncRNA HOTAIR, LncRNA H19, and other classical LncRNAs could regulate the self-renewal and malignant transformation of CSCs through different mechanisms in different tumors. In general, the abnormal differentiation of CSCs is crucial to metastasis and recurrence in a variety of tumors, and LncRNAs play important roles in the abnormal differentiation of CSCs. However, up to now, the researches on cancer stem cells and LncRNAs have been focused on the influence of LncRNAs aberrant expression on cancer stem cells’ malignant transformation, but few studies have explored how LncRNAs change in the tumor environment. In the future, if we can clarify the relevant mechanisms, it will provide us with new ideas. We believe that the multiple functions of LncRNAs suggest that they may become novel promising targets to eradicate tumor stem cells, which may provide a new possibility for curative treatments of numerous cancers.
Cancer stem cells
Epithelial mesenchymal transition
Long intergenic ncRNAs
Long non-coding RNAs
This work was supported by the National Natural Science Foundation of China (Nos. 81270607, 81400121, and 81541027). The funding allowed the collection and analysis of data.
Availability of data and materials
The data and material that support the conclusions of this review have been included within the article.
XH drafted the manuscript. RX performed the selection of literature. SP, XY, and WY collected the related references. ZT, MX, YZ, and QY prepared the figures. YW, WH, LS, and JX revised the language. QZ carried out the design of the review. All authors contributed to this manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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