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Supporting data for "The role of lumican in hepatocellular carcinoma"

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posted on 15.09.2021, 06:30 by Cheuk Yan WongCheuk Yan Wong
Hepatocellular carcinoma (HCC) remains a worldwide health challenge with its incidence rising globally. Locoregional therapies is still the mainstay for HCC treatment, however, majority of the HCC patients are diagnosed at advanced stage where palliative therapies are the only options, and the rate of recurrence appears to be high. With the rapid expanding knowledge in the pathogenic mechanism of HCC, new promising therapeutic approaches including immunotherapy, targeted therapy and combination therapies have been introduced. While the emergence of these novel therapies has offered hope to HCC patients, they are effective in providing limited clinical benefit, and some are even yet to be translated into clinical setting owing to the lack of efficacy. Metastasis is a predominant cause of death in patients due to multiple organ failure, and it is often observed in patients with advanced stage HCC. Thus, the identification of key players in HCC metastasis would help discovering new potential therapeutic targets and combating HCC by filling the unmet need for effective treatment.

Lumican (LUM) is an extracellular matrix protein that has a well-established role in collagen fibril assembly. In the liver, LUM was shown to be a prerequisite for hepatic fibrosis, and it was overexpressed in liver tissues of patients with chronic hepatitis B, fibrosis and non-alcoholic steatohepatitis (NASH). Intriguingly, it was revealed as a double-edged sword in cancer pathogenesis, in which it could be both pro-tumorigenic and anti-tumorigenic dependig on the tumour origin. A Chinese literature by Mu et al. demonstrated that the migratory and invasive potentials of HCC cells were attenuated by silencing the LUM gene, which implied a pro-tumorigenic role of LUM in HCC. Yet, as a secreted protein, the functional role and clinical significance of secreted LUM (sLUM) in HCC is largely unexplored. Therefore, we focused on assessing the clinical significance of sLUM in HCC and elucidating the functional implication of sLUM in the metastasis of HCC in this study.

In the clinical cohorts, our study revealed that LUM was upregulated in both tumoral and non-tumoral regions of fibrotic liver tissues from HCC patients, with fibroblasts in the stromal area as a main source of sLUM. Moreover, a high serum level of LUM was associated with more aggressive pathological features of HCC and poor prognosis. It as well further stratified the overall survival of patients when used in combination with other HCC prognosticators, which suggested a potential role of sLUM as an HCC prognostic marker. At molecular level, in consistence with the clinical results, LUM was overexpressed in HCC cell lines and normal liver fibroblast (NLF), with fibroblast secreted the most abundant LUM among all human cell lines. By means of the recombinant human LUM protein (rhLUM) and the NLF-derived conditioned medium, sLUM enhanced the metastatic and self-renewal potentials of HCC which could be antagonised by the anti-LUM antibody. Similarly, through co-culture of HCC cells and LUM-knockdown NLF, the metastatic and self-renewal abilities of tumour cells was significantly reduced. In summary, sLUM is a potential therapeutic target and prognostic biomarker for HCC.

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