Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly malignant gastrointestinal cancer with a high recurrence rate and poor prognosis. Although N6-methyladenosine (m6A), the most abundant epitranscriptomic modification of mRNAs, has been implicated in several cancers, little is known about its participation in ESCC progression. We found reduced expression of ALKBH5, an m6A demethylase, in ESCC tissue specimens with a more pronounced effect in T3-T4, N1-N3, clinical stages III–IV, and histological grade III tumors, suggesting its involvement in advanced stages of ESCC. Exogenous expression of ALKBH5 inhibited the in vitro proliferation of ESCC cells, whereas depletion of endogenous ALKBH5 markedly enhanced ESCC cell proliferation in vitro. This suggests ALKBH5 exerts anti-proliferative effects on ESCC growth. Furthermore, ALKBH5 overexpression suppressed tumor growth of Eca-109 cells in nude mice; conversely, depletion of endogenous ALKBH5 accelerated tumor growth of TE-13 cells in vivo. The growth-inhibitory effects of ALKBH5 overexpression are partly attributed to a G1-phase arrest. In addition, ALKBH5 overexpression reduced the in vitro migration and invasion of ESCC cells. Altogether, our findings demonstrate that the loss of ALKBH5 expression contributes to ESCC malignancy.
Highlights
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive histological subtype of esophageal cancer reported in Asia, with China having one of the highest morbidity and mortality rates [1,2,3]
To study the involvement of ALKBH5 in ESCC progression, we first checked the expression of ALKBH5 protein in 206 paraffin-embedded, archived ESCC specimens and 31 adjacent non-cancerous tissues (NT) by immunohistochemistry (IHC)
No association was identified between ALKBH5 expression and age (P = 0.524) and sex (P = 1.000) using 206 ESCC samples (Table 2), ALKBH5 expression was inversely correlated with tumor size (T classification; P = 0.006), lymph node invasion (N classification, P = 0.019), clinical stage (I–II versus III–IV, P = 0.027), and histological grade (P = 0.023) in these patients (Figure 1E, 1F and Table 2)
Summary
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive histological subtype of esophageal cancer reported in Asia, with China having one of the highest morbidity and mortality rates [1,2,3]. The mainstay of treatment includes surgical resection, radiotherapy, and chemotherapy [1,2,3]; these are associated with unsatisfactory clinical outcomes due to adverse effects and limited efficacy. A detailed understanding of ESCC immunobiology would be useful in developing efficient prognostic biomarkers and therapeutic targets that can detect the tumor at an early stage, resulting in early diagnosis and treatment. The effect on target mRNAs depends on the activity of m6A-binding proteins (readers)—YTH domain-containing family proteins YTHDF1/2/3, YTHDC1, and YTHDC2; RNA-binding proteins—that have been implicated in several aspects of mRNA metabolism, including mRNA splicing, localization, translation, and decay [4,5,6,7]. The m6A modification on mRNAs regulates several physiological and pathological processes such as embryonic stem cell fate [8, 9], somatic cell reprogramming and pluripotency [10], hematopoietic stem/progenitor cell lineage specification and differentiation [11,12,13], axon regeneration [14], sex determination [15, 16], T cell homeostasis [17], innate immunity [18], DNA damage [19], and spermatogenesis [20]
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