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Long non-coding RNA HOTTIP affects renal cell carcinoma progression by regulating autophagy via the PI3K/Akt/Atg13 signaling pathway

  • Original Article – Cancer Research
  • Published:
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Abstract

Objective

Renal cell carcinoma (RCC) is the most common malignancy of the urinary system, and it is a serious threat to human health. HOXA transcript at the distal tip (HOTTIP), located at the 5′ end of the HOXA locus, is a long non-coding RNA that has been newly discovered in recent years. It has been reported to promote the development of several types of tumors. Moreover, accumulating evidence has indicated that autophagy plays an important role in tumor cell survival or death. However, whether HOTTIP affects RCC development by regulating autophagy remains unknown.

Methods

In this study, we first measured HOTTIP expression in 42 paired RCC and adjacent non-tumor tissues, as well as in 4 RCC cell lines and 1 normal renal tubular epithelial cell line. Then, we selected 2 RCC cell lines to silence HOTTIP expression and 1 RCC cell line to overexpress HOTTIP, and we measured their proliferation, migration and invasion, as well as autophagy, after pretreatment with an autophagy inhibitor or inducer. In addition, we assessed the growth, metastasis and autophagy of tumors in nude mice and explored the mechanism involved.

Results

The results showed that HOTTIP expression was significantly upregulated in the RCC tissues and cell lines, and it was closely associated with TNM stage, histological grade, lymph node metastasis and patient prognosis. The in vitro and in vivo assays indicated that HOTTIP silencing inhibited RCC cell proliferation, migration and invasion and induced autophagy, and 3-MA (an autophagy inhibitor) reversed these effects. In contrast, HOTTIP overexpression and rapamycin (an autophagy inducer) yielded the opposite results. Further research revealed that HOTTIP modification could affect RCC cell autophagy via the PI3K/Akt/Atg13 signaling pathway.

Conclusions

Our study will help in finding a potential marker for RCC diagnosis and supply a target molecule for RCC treatment.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81470923, 81470986, 81770078 and 81770688).

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Authors and Affiliations

  1. Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yang Su, Jingxiao Lu, Cong Qin & Jie Zhang

  2. Huangshi Central Hospital, Hubei Polytechnic University, Huangshi, 435000, China

    Pengcheng Luo & Jie Zhang

  3. Department of Urology, First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China

    Xianguo Chen & Chaozhao Liang

Authors
  1. Yang Su
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  2. Jingxiao Lu
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  6. Cong Qin
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  7. Jie Zhang
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Correspondence to Jie Zhang.

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The authors declared that no conflict of interest exists.

Ethical approval

This study was approved by the Ethical Committee of Renmin Hospital of Wuhan University. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and all procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Su, Y., Lu, J., Chen, X. et al. Long non-coding RNA HOTTIP affects renal cell carcinoma progression by regulating autophagy via the PI3K/Akt/Atg13 signaling pathway. J Cancer Res Clin Oncol 145, 573–588 (2019). https://doi.org/10.1007/s00432-018-2808-0

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