Renal cell carcinoma (RCC) is considered one of the most widespread cancers affecting humans [1]. It is estimated that nearly 25% of all patients with clear cell RCC (ccRCC) will relapse after surgery. Most ccRCCs are associated with mutations in the von Hippel-Lindau (VHL) tumor suppressor, inducing the expression of the transcription factor hypoxia-inducible factor 1α (HIF1α), thereby affecting the metabolic activity of the tumor [2]. Hypoxic gene expression downstream of HIF1α is considered one of the main driving forces of RCC [3]. Interestingly, HIF1α has previously been reported as a tumor suppressor in ccRCC [4]. However, some reports suggest that the deletion of HIF1α counteracts the tumor-promoting effect caused by the omission of VHL [5]. Furthermore, several studies have demonstrated a correlation between HIF1α and highly invasive or high-grade renal cancers, indicating that macrophage HIF1α may be an independent prognostic indicator for RCC [6].

Long non-coding RNAs (lnc-RNAs) contain 200 nucleotides (nt) or more and do not contain any protein-coding sequences. Lnc-RNA is essential in many bio-physiological functions, including gene regulations via transcriptional and posttranscriptional mechanisms [7]. Recently, lnc-RNAs have been implicated in the metastasis and invasion of many types of cancers, such as medulloblastoma, gynecological, colorectal, and breast cancers [8], [9], [10], [11]. Several regulatory mechanisms of lnc-RNAs in RCC have been reported. For example, it has been proposed that loss of VHL affects lncRNA PVT1 and increases its expression, thereby regulating ccRCC proliferation [11]. LINC00461 is significantly up-regulated in RCC and is associated with sunitinib resistance [12]. Increased expression of Small nucleolar RNA host gene-4 (SNHG4) has been reported in RCC, significantly correlated with T stage, lymph node involvement, and distant metastasis [13]. hypoxia-inducible factor 1α (HIF1α)-antisense RNA 2 (AS2) or HIF1A-AS2 is encoded as an antisense transcript of HIF1α. It is located on chromosome 14q23.2 [14]. It regulates a variety of cancers, including colorectal, gastric, and bladder [15], [16], [17]. From previous reports, HIF1A-AS2 affects ccRCC by regulating the mir-130a-5p/ ERBB2 pathway [18] and the mir-30a-5p/SOX4 axis [19]. This study aims to provide additional evidence on the regulatory role and invasive function of HIF1A-AS2 in ccRCC.